Treatment of sleep loss or sleep disorder in dermatitis patients

Abstract

An anti-IL-13R [alpha] 1 antibody, or antigen-binding fragment thereof, and a pharmaceutical formulation comprising said anti-IL-13R [alpha] 1 antibody, or antigen-binding fragment thereof, for use in the treatment of a patient suffering from a skin disorder, such as atopic dermatitis, subject to sleep insufficiency or sleep disorder caused by pruritus. Also provided is a method of treating sleep insufficiency or sleep disorder caused by pruritus in said patient, the method comprising administering to a patient in need thereof an anti-IL-13R [alpha] 1 antibody or an antigen-binding fragment thereof or a pharmaceutical formulation comprising said anti-IL-13R [alpha] 1 antibody or an antigen-binding fragment thereof.

Description

[0001] The present invention relates to the use of an anti-interleukin-13 receptor alpha 1 (IL-13Rα1) antibody or a binding fragment thereof, and a pharmaceutical preparation comprising the same, for treating patients experiencing sleep deprivation or sleep disorders. Background Art

[0002] It is common for all individuals to occasionally experience sleep insufficiency or sleep disorders, for example due to stress and anxiety, shift work that may disrupt the sleep cycle, the use of certain drugs, etc. However, a subset of individuals, such as highly allergic patients, often experience sleep insufficiency or sleep disorders due to their underlying medical conditions.

[0003] Highly allergic patients often suffer from skin diseases such as atopic dermatitis or eczema. Chronic pruritus is a hallmark and major symptom of atopic dermatitis and other type 2 inflammation-driven skin diseases. Thus, these conditions may make it particularly difficult for these patients to fall asleep or stay asleep due to the discomfort experienced on a daily basis.

[0004] Recently, it has been proposed that pruritus signaling in atopic dermatitis (AD) is exacerbated by the presence of pro-inflammatory cytokines in the skin, which triggers an immune response, disrupts the skin barrier, and promotes disease pathology. For certain cytokines, such as interleukin-31 (IL-31) and interleukin-4 (IL-4), their roles in pruritus signaling have been well documented. However, for other cytokines, such as interleukin-13 (IL-13), there is less evidence of its direct role in pruritus pathophysiology.

[0005] One way to inhibit the activity of interleukin-13 (IL-13) is to interfere with the binding of IL-13 to its receptor IL-13R, for example by using a specific antibody against IL-13R, such as a specific antibody against IL-13Rα1. An effective antibody antagonist against IL-13Rα1 may also interfere with the binding of IL-13 and prevent the formation of heterodimers between IL-4Rα and IL-13Rα1. Such an antibody can inhibit the signaling of IL-13 and IL-4 through the type II receptor, while not affecting the signaling of IL-4 through the type I receptor. During the induction phase of the immune response, during Th2 cell differentiation, signaling through the type I receptor is crucial. T cells do not express IL-13Rα1, so the type II receptor does not play a role in Th2 cell differentiation. Thus, an IL-13Rα1 antibody should not affect the overall Th1 / Th2 balance. During the effector A phase of the immune response, during an established allergic inflammation process, signaling through the type II IL-4 / IL-13 receptor is crucial. Thus, blocking the type II receptor should have a beneficial effect on many of the symptoms of diseases mediated by IL-13R and is therefore an effective disease-improving agent.

[0006] Antibodies (including monoclonal and polyclonal antibodies) against interleukin-13 receptor α1 (IL-13Rα1) have been described in the prior art; for example, see International Patent Application Publication Nos. WO 97 / 15663, WO 03 / 80675, WO 03 / 46009, WO 06 / 072564; Gauchat et al., 1998, European Journal of Immunology, Vol. 28, pp. 4286-4298; Gauchat et al., 2000, European Journal of Immunology, Vol. 30, pp. 3157-3164; Clement et al., 1997, Cytokine, Vol. 9 (No. 11): 959 (conference abstract); Ogata et al., 1998, Journal of Biological Chemistry, Vol. 273: pp. 9864-9871; Graber et al., 1998, European Journal of Immunology, Vol. 28, pp. 4286-4298; C. Vermot-Desroches et al., 2000, Tissue Antigens, Vol. 5 (Suppl. 1): pp. 52-53 (conference abstract); Poudrier et al., 2000, European Journal of Immunology, Vol. 30, pp. 3157-3164; Akaiwa et al., 2001, Cytokine, Vol. 13: pp. 75-84; Cancino-Diaz et al., 2002, Journal of Investigative Dermatology, Vol. 119, pp. 1114-1120; and Krause et al., 2006, Molecular Immunology, Vol. 43, pp. 1799-1807.

[0007] A particularly promising anti - interleukin - 13 receptor alpha 1 (IL - 13Rα1) antibody is described as antibody 10G5 - 6 in International Patent Application Publication No. WO2008 / 060813. 10G5 - 6 is an IgG4 antibody with a stabilizing mutation in its hinge region from serine to proline (S241P according to the Kabat numbering system). This antibody is now known as ixekizumab (previously known as ASLAN004, and the two names can be used interchangeably here). Ixekizumab has been shown to bind with high affinity to the human interleukin - 13 receptor alpha 1 (IL - 13Rα1) (e.g., the dissociation constant Kd may be 500 picomoles). Ixekizumab has been demonstrated to effectively antagonize the function of interleukin - 13 by inhibiting the binding of interleukin - 13 to its receptor interleukin - 13 receptor alpha 1 (IL - 13Rα1), and can inhibit the release of eosinophil chemotactic factor induced by interleukin - 13 and interleukin - 4 in human neonatal foreskin fibroblasts (NHDF), inhibit the phosphorylation of STAT6 induced by interleukin - 13 and interleukin - 4 in human neonatal foreskin fibroblasts (NHDF), and inhibit the release of thymus - activated regulated chemokine (TARC) in interleukin - 13 - stimulated blood or peripheral blood monocytes.

[0008] It is well known that chronic sleep deprivation can lead to impaired cognitive ability, increased irritability, and daytime sleepiness, all of which have a significant negative impact on quality of life. In addition, the cumulative long - term effects of sleep deprivation and sleep disorders are also associated with a series of harmful health consequences, such as an increased risk of developing diabetes, depression, heart attack, and stroke.

[0009] Therefore, there is a need for alternative treatment methods to control and treat sleep deprivation or sleep disorders, such as those in highly allergic patients. SUMMARY OF THE INVENTION

[0010] The following paragraphs summarize the present invention:

[0011] 1. An antibody or an antigen - binding fragment thereof that inhibits signal transduction by binding to interleukin - 13 receptor alpha 1 (IL - 13Rα1) for treating sleep deprivation or sleep disorders in a patient by parenteral administration for one treatment cycle (dose range from 200 mg to 600 mg, such as 300, 400, 500, or 600 mg, e.g., 400 to 600 mg). For example, the treatment can reduce the sleep disorder (SD) score in the Patient - Oriented Eczema Measure (POEM), e.g., by - 50% to - 100% relative to the baseline, such as a reduction of 2 to 4 points relative to the baseline.

[0012] 1A. An antibody or antigen-binding fragment thereof that inhibits signal transduction by binding to interleukin-13 receptor alpha 1 (IL-13Rα1) and is used to reduce the sleep disturbance (SD) score on the Patient-Oriented Eczema Measure (POEM), for example, reducing the sleep disturbance score by 50% to 100%, such as a reduction of 2 to 4 points compared to baseline, for patients with sleep deprivation, by parenteral administration, with a dose range of 200 mg to 600 mg (such as 400 to 600 mg) for one treatment cycle.

[0013] 1B. An antibody or antigen-binding fragment thereof that inhibits signal transduction by binding to interleukin-13 receptor alpha 1 (IL-13Rα1) and is used to reduce the sleep deprivation component of the SCORing Atopic Dermatitis (SCORAD), for example, a reduction of 20% to 100% compared to baseline, such as a reduction of 2 points or more, for example, a reduction of 2, 3, 4, 5, 6, 7, 8, 9, or 10 points compared to baseline.

[0014] 1C. An antibody or antigen-binding fragment thereof that inhibits signal transduction by binding to interleukin-13 receptor alpha 1 (IL-13Rα1) and is used to reduce the score on the Sleep Disturbance Numerical Rating Scale (SD NRS), for example, a reduction of 20% to 100% compared to baseline, such as a reduction of 4 points or more compared to baseline, for example, a reduction of 4, 5, 6, 7, 8, 9, or 10 points compared to baseline.

[0015] 2. The antibody or antigen-binding fragment thereof according to any one of the preceding paragraphs, wherein the treatment reduces the sleep disturbance (SD) score on the Patient-Oriented Eczema Measure (POEM), for example, a reduction of 50% to 100% compared to baseline, such as a reduction of 2 to 4 points compared to baseline.

[0016] 3. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient's baseline sleep disturbance (SD) score is at least 3 points, such as 3 or 4 points.

[0017] 4. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient's baseline sleep disturbance (SD) score is 3.

[0018] 5. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient's baseline sleep disturbance (SD) score is 4.

[0019] 6. An antibody or antigen-binding fragment thereof for use according to any one of the preceding paragraphs, wherein the SD score is reduced by 2 to 4 points compared to baseline, for example, reduced by 2, 3, or 4 points.

[0020] 7. The antibody or antigen-binding fragment thereof for use according to any one of the preceding paragraphs, wherein the sleep disturbance (SD) score is reduced by 2 points compared to baseline.

[0021] 8. An antibody or antigen-binding fragment thereof used as described in any of the preceding paragraphs, wherein the sleep disorder (SD) score is reduced by 3 points compared to the baseline.

[0022] 9. An antibody or antigen-binding fragment thereof used as described in any of the preceding paragraphs, wherein the sleep disorder (SD) score is reduced by 4 points compared to the baseline.

[0023] 10. An antibody or antigen-binding fragment thereof for use as described in any of the preceding paragraphs, wherein the SD score is reduced by at least 50% compared to the baseline, for example, reduced by 2 points from a baseline SD score of 4 points.

[0024] 11. An antibody or antigen-binding fragment thereof used as described in any of the preceding paragraphs, wherein the sleep disorder score is reduced by at least 66% compared to the baseline. For example, if the baseline sleep disorder score is 3 points, it is reduced by 2 points.

[0025] 12. An antibody or antigen-binding fragment thereof for treatment as described in any of the preceding paragraphs, wherein the sleep disorder (SD) score is reduced by at least 75% compared to the baseline. For example, if the baseline SD score is 4 points, it is reduced by 3 points.

[0026] 13. An antibody or antigen-binding fragment thereof for treatment as described in any of the preceding paragraphs, wherein the sleep disorder (SD) score is reduced by 100% compared to the baseline. For example, if the baseline SD score is 2 points, it is reduced by 2 points; if the baseline SD score is 3 points, it is reduced by 3 points; or if the baseline SD score is 4 points, it is reduced by 4 points.

[0027] 14. An antibody or antigen-binding fragment thereof for treatment as described in any one of paragraphs 1 to 13, wherein the treatment results in a reduction in the sleep deprivation component of the Scoring Atopic Dermatitis (SCORAD) index, for example, a reduction of -20% to -100% compared to the baseline, such as a reduction of 2 to 10 points compared to the baseline.

[0028] 15. An antibody or antigen-binding fragment thereof for treatment as described in paragraph 14, wherein the treatment results in a reduction in the sleep deprivation component of the Scoring Atopic Dermatitis (SCORAD) index of at least -30% compared to the baseline, such as a reduction of -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%.

[0029] 16. An antibody or antigen fragment thereof for treatment as described in paragraph 14 or 15, wherein the sleep deprivation part of the SCORAD is reduced by -35% to -55% compared to the baseline, for example, reduced by -35%, -40%, -50% or -55%.

[0030] 17. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 14 to 16, wherein the treatment results in a reduction of 4 points or more in the sleep deprivation component of SCORAD compared to baseline, such as a reduction of 4, 5, 6, 7, 8, 9, or 10 points.

[0031] 18. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 17, wherein the baseline score of the sleep deprivation component in the patient's Severity Scoring of Atopic Dermatitis (SCORAD) is at least 4 points, such as 4, 5, 6, 7, 8, 9, or 10 points.

[0032] 19. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 18, wherein the treatment results in a reduction in the score of the Sleep Disturbance Numerical Rating Scale (SD NRS), such as a reduction of -20% to -100% compared to baseline, e.g., a reduction of 2 to 10 points compared to baseline.

[0033] 20. An antibody or antigen-binding fragment thereof for treatment according to paragraph 19, wherein the treatment results in a reduction of at least -30% in the Sleep Disturbance Numerical Rating Scale (SD NRS) compared to baseline, such as a reduction of -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95%, or -100%.

[0034] 21. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 19 to 20, wherein the treatment results in a reduction of 4 points or more in the Sleep Disturbance Numerical Rating Scale (SD NRS) relative to baseline, such as 4, 5, 6, 7, 8, 9, or 10 points.

[0035] 22. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 21, wherein the baseline score of the patient's Sleep Disturbance Numerical Rating Scale (SD NRS) is at least 4 points, such as 4, 5, 6, 7, 8, 9, or 10 points.

[0036] 23. An antibody or antigen-binding fragment thereof for treatment according to any of the preceding paragraphs, wherein the patient is a highly allergic patient, e.g., in such patients, a baseline immunoglobulin E (IgE) level has been determined and the level is at least 10,000 KU / L ± 2,000.

[0037] 24. An antibody or antigen-binding fragment thereof used according to paragraph 23, wherein the baseline immunoglobulin E (IgE) level is in the range of 10,000 ± 2,000 to 30,000 ± 6,000 KU / L.

[0038] 25. An antibody or antigen-binding fragment thereof used as described in any one of paragraphs 23 to 24, wherein the treatment reduces the immunoglobulin E (IgE) level by at least 15% compared to the baseline.

[0039] 26. The antibody or binding fragment for treatment according to paragraph 25, wherein the treatment reduces the IgE level by at least 20% relative to the baseline.

[0040] 27. The antibody or its binding fragment for treatment according to paragraph 25 or 26, wherein the treatment reduces the immunoglobulin E (IgE) level by at least 30% compared to the baseline, for example, reduces the level by 30% to 40% compared to the baseline, and the degree of reduction is, for example, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40% of the baseline level.

[0041] 28. The antibody or binding fragment according to any one of paragraphs 1 to 27, wherein symptom relief can be observed approximately on day 15.

[0042] 29. The antibody or binding fragment according to any one of paragraphs 1 to 27, wherein symptom relief can be observed approximately on day 29.

[0043] 30. The antibody or binding fragment according to any one of paragraphs 1 to 27, wherein symptom relief can be observed approximately on day 57.

[0044] 31. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has pruritus.

[0045] 32. The antibody or antigen-binding fragment thereof for treatment according to paragraph 21, wherein the pruritus is mediated by one or more of the following substances: histamine, serotonin, acetylcholine, substance P (SP), leukotrienes, bradykinin, proteases (such as trypsin, tryptase, cathepsin S or kallikrein-related peptidases such as KLK4 or KLK14), interleukin-31, lysophosphatidic acid, autotaxin and / or Toll-like receptor 7 (TLR7).

[0046] 33. The antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 31 to 32, wherein the pruritus is mediated by histamine.

[0047] 34. The antibody or antigen-binding fragment thereof used as described in any one of paragraphs 31 to 33, wherein the pruritus is mediated by interleukin-13 (IL-13), interleukin-4 (IL-4) or a combination of both.

[0048] 35. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 31 to 34, wherein the pruritus is jointly mediated by interleukin-13 (IL-13) and interleukin-4 (IL-4).

[0049] 36. An antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has a skin disease, such as selected from the group consisting of: dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis; eczema; hand, foot and mouth disease; urticaria (including urticaria associated with lupus), psoriasis, infections, such as fungal infections or bacterial infections, such as impetigo or folliculitis; allergic skin reactions; Ehlers-Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE).

[0050] 37. An antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis.

[0051] 38. An antibody or antigen-binding fragment thereof for the application according to any one of the preceding paragraphs, wherein the patient has atopic dermatitis (AD), such as moderate to severe atopic dermatitis.

[0052] 39. An antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has Ehlers-Danlos syndrome (EDS), asthma or angioedema (such as hereditary angioedema).

[0053] 40. An antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has asthma.

[0054] 41. An antibody or antigen-binding fragment thereof for treatment according to any one of the preceding paragraphs, wherein the patient has angioedema.

[0055] 42. An antibody or antigen-binding fragment thereof used according to any one of paragraphs 1 to 41, wherein the patient does not have atopic dermatitis or psoriasis.

[0056] 43. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 42, wherein the patient does not have atopic dermatitis.

[0057] 44. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 42, wherein the patient does not have psoriasis.

[0058] 45. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 44, wherein the patient has previously received dupilumab treatment.

[0059] 46. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 45, wherein the patient has insufficient sleep or a sleep disorder and the control effect using dupilumab is poor.

[0060] 47. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 46, wherein the patient has atopic dermatitis and has insomnia or a sleep disorder that is still poorly controlled after treatment with dupilumab.

[0061] 48. An antibody or antigen-binding fragment thereof for treatment according to any one of the foregoing paragraphs, about two weeks after the first administration (e.g., day 15), there will be a decrease in the sleep disorder (SD) score, the sleep deprivation part of the SCORAD (Severity of Atopic Dermatitis Index) or the score of the Sleep Disorder Numerical Rating Scale (SD NRS).

[0062] 49. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 47, wherein about four weeks after the first administration (such as day 29), the severity score (SD score), the score of the sleep deprivation part of the SCORAD or the score of the Severity Numerical Rating Scale (SD NRS) decreases.

[0063] 50. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 57, wherein about six weeks after the first administration (such as day 43), the severity score (SD score), the score of the sleep deprivation part in the SCORAD or the score of the Sleep Disorder Numerical Rating Scale (SD NRS) decreases.

[0064] 51. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 57, wherein about eight weeks after the first administration (such as day 57), the severity score (SD score), the score of the sleep deprivation part of the SCORAD or the score of the Sleep Disorder Numerical Rating Scale (SD NRS) decreases.

[0065] 52. An antibody or antigen-binding fragment thereof for treatment according to any one of the foregoing paragraphs, wherein the treatment is administered by intravenous injection.

[0066] 53. An antibody or antigen-binding fragment thereof for treatment according to any one of paragraphs 1 to 51, wherein the treatment is administered by subcutaneous injection.

[0067] 54. An antibody or antigen-binding fragment thereof for use according to any one of the foregoing paragraphs, wherein multiple administrations are performed within one treatment cycle (for example, the treatment cycle is 4 to 8 weeks, such as 8 weeks).

[0068] An antibody or antigen-binding fragment thereof for use according to any of the preceding paragraphs, wherein multiple treatment cycles are carried out, for example, 2, 3, 4 or more treatment cycles are carried out.

[0069] 56. An antibody or antigen-binding fragment thereof for use in treatment according to paragraph 41 or 42, after one or more treatment cycles and improvement of the disease, maintenance treatment is carried out, for example, the same dose is administered at a lower dosing frequency (such as once a month), or a lower dose (such as 200 mg) is administered at the same or a lower dosing frequency (such as approximately once every two weeks, once every three weeks or once every four weeks).

[0070] 57. An antibody or antigen-binding fragment thereof for use according to any of the preceding paragraphs, wherein the antibody or its binding fragment is administered approximately once a week (especially in a single treatment cycle, particularly an 8-week treatment cycle).

[0071] 58. An antibody or antigen-binding fragment thereof for use according to any of paragraphs 1 to 55, wherein the antibody or its binding fragment is administered approximately once every two weeks (especially in a single treatment cycle, particularly an 8-week treatment cycle).

[0072] 59. An antibody or antigen-binding fragment thereof for use according to any of paragraphs 1 to 55, wherein the antibody or its binding fragment is administered approximately once every three weeks (especially in a single treatment cycle, particularly an 8-week treatment cycle).

[0073] 60. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 1 to 55, wherein the antibody or binding fragment is administered approximately once every four weeks (such as once a month) (especially in a single treatment cycle, particularly 8 weeks).

[0074] 61. An antibody or antigen-binding fragment thereof for use according to any of the preceding paragraphs, wherein a loading dose in the range of 400 to 900 mg is used before administration in a treatment cycle, for example, 400, 500, 600, 700, 800 or 900 mg.

[0075] 62. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 1 to 61, wherein a loading dose of 600 mg is administered before the treatment dose.

[0076] 63. An antibody or antigen-binding fragment thereof for use according to paragraph 61 or 62, wherein the loading dose is administered for 1 to 3 weeks before the treatment dose, for example, 1, 2 or 3 weeks.

[0077] 64. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 61 to 63, wherein the loading dose is administered only at week 0, for example, 600 mg is administered at week 0.

[0078] An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 61 to 63, wherein a loading dose is administered at week 0 and week 1, for example, 600 mg is administered at week 0 and 600 mg is administered at week 1.

[0079] 66. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 61 to 65, wherein a loading dose is administered at week 0, week 1, and week 2, for example, 600 mg is administered at week 0, 600 mg is administered at week 1, and 600 mg is administered at week 2

[0080] 67. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 1 to 60, wherein the treatment regimen does not include a loading dose.

[0081] 68. An antibody or antigen-binding fragment thereof for use in treatment according to any of the preceding paragraphs, wherein the dose is 200 mg.

[0082] 69. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 67, wherein the dose is 300 mg, for example, administered once every two weeks.

[0083] 70. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 67, wherein the dose is 400 mg, for example, administered once every two weeks or once a month.

[0084] 71. An antibody or antigen-binding fragment thereof for use in treatment according to any one of paragraphs 1 to 67, wherein the dose is 600 mg, for example, administered once a month.

[0085] 72. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein the therapeutic dose of the anti-interleukin-13 receptor (IL13R) antibody or its binding fragment is 400 mg administered every 2 weeks (400 mg Q2W).

[0086] 73. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein the therapeutic dose of the anti-interleukin-13 receptor (IL13R) antibody or its binding fragment is 600 mg administered every 2 weeks (600 mg Q2W).

[0087] 74. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein the therapeutic dose of the anti-interleukin-13 receptor (IL13R) antibody or its binding fragment is 300 mg administered every 2 weeks (300 mg Q2W).

[0088] An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein a loading dose of 600 mg is administered at week 0 and week 1, followed by a therapeutic dose of 300 mg every two weeks (300 mg, once every two weeks).

[0089] 76. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein a loading dose of 600 mg is administered at week 0 and week 1, followed by a therapeutic dose of 400 mg every two weeks (400 mg, once every two weeks).

[0090] 77. An antibody or antigen-binding fragment thereof for use according to any one of paragraphs 1 to 71, wherein a loading dose of 600 mg is administered at weeks 0, 1 and 2, followed by a therapeutic dose of 600 mg every four weeks (400 mg, once every four weeks).

[0091] 78. An antibody or antigen-binding fragment thereof for use according to any one of the preceding paragraphs, wherein the treatment cycle comprises: a first dose of 600 mg, followed by weekly doses of 400 mg for three consecutive weeks. For example, this treatment cycle is repeated twice, i.e., the two treatment cycles last for a total of 8 weeks. Specifically, 600 mg is administered on day 1, approximately 400 mg is administered on day 8, approximately 400 mg is administered on day 15, approximately 400 mg is administered on day 22, approximately 600 mg is administered on day 29, approximately 400 mg is administered on day 36, approximately 400 mg is administered on day 43, and approximately 400 mg is administered on day 50.

[0092] 79. An antibody or antigen-binding fragment thereof for use according to any one of the preceding paragraphs, wherein improvement in the condition occurs on day 8, where day 1 is the first administration of the antibody or its binding fragment.

[0093] 80. An antibody or antigen-binding fragment thereof for use according to any one of the preceding paragraphs, wherein the improvement in the condition is manifested as a decrease in the standard deviation score of patient-oriented outcome measures (POEM). For example, this decrease is a percentage compared to the baseline and is in the range of -50% to -100%.

[0094] 81. An antibody or antigen-binding fragment thereof for use according to paragraph 80, wherein improvement in the condition in the range of -50% to -100% is achieved approximately on day 57 after the first administration on day 1. For example, maximum improvement in the condition is achieved approximately on day 57.

[0095] An antibody or antigen-binding fragment thereof for use according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment binds to the epitope FFYQ (e.g., binds to the same epitope as an antibody having a heavy chain variable region (VH) as shown in SEQ ID NO: 51 and a light chain variable region (VL) as shown in SEQ ID NO: 53, or binds to the same epitope as a sequence having at least 95% identity to either of them).

[0096] An antibody or antigen-binding fragment thereof for use according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment is an anti-interleukin 13 receptor alpha 1 (IL-13Rα1) antibody or antigen-binding fragment thereof.

[0097] An antibody or antigen-binding fragment thereof for use in treatment according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment comprises a heavy chain complementarity determining region 1 (VH CDR1) having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (VH CDR2) having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (VH CDR3) having the amino acid sequence shown in SEQ ID NO: 10.

[0098] An antibody or antigen-binding fragment thereof for use in treatment according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment comprises a VH domain that comprises the amino acid sequence shown in SEQ ID NO: 51 or a sequence having at least 95% identity thereto, particularly SEQ ID NO: 51.

[0099] An antibody or antigen-binding fragment thereof for use in treatment according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment comprises a light chain complementarity determining region 1 (VL CDR1) having the amino acid sequence shown in SEQ ID NO: 31, a light chain complementarity determining region 2 (VL CDR2) having the amino acid sequence shown in SEQ ID NO: 32, and a light chain complementarity determining region 3 (VL CDR3) having the amino acid sequence shown in SEQ ID NO: 45.

[0100] An antibody or antigen-binding fragment thereof for use in treatment according to any of the preceding paragraphs, wherein the antibody or antigen-binding fragment comprises a VL domain that comprises the amino acid sequence shown in SEQ ID NO: 53 or a sequence having at least 95% identity thereto, particularly SEQ ID NO: 53.

[0101] 88. An antibody or antigen-binding fragment thereof for treatment according to any of the preceding paragraphs, wherein the antibody comprises a light chain variable region (VL) having the amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, particularly SEQ ID NO: 53, and a heavy chain variable region (VH) having the amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, particularly SEQ ID NO: 51.

[0102] 89. A pharmaceutical formulation comprising an antibody or binding fragment thereof for treatment according to any of paragraphs 1 to 88, the formulation comprising 150 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, such as 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 or 210 mg / ml, particularly 150 mg / ml, 175 mg / ml or 200 mg / ml;

[0103] 170 to 250 millimoles of arginine (such as arginine hydrochloride or arginine glutamate), such as 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 millimoles, particularly 150 millimoles, 175 millimoles or 250 millimoles;

[0104] 20 to 50 millimoles of histidine buffer, such as 20, 25, 30, 35, 40, 45 or 50 millimoles, such as 20 millimoles or 50 millimoles of histidine buffer;

[0105] 0.01 - 0.03% of a non-ionic surfactant, such as 0.02% w / w; and

[0106] wherein the pH of the formulation is in the range of 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, especially 6.5.

[0107] 90. A pharmaceutical formulation comprising an antibody or binding fragment thereof for treatment according to any of paragraphs 1 to 88, the formulation comprising 175 to 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, such as 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 or 225 mg / ml, particularly 200 mg / ml, 225 mg / ml or 250 mg / ml;

[0108] 15 to 75 millimoles of tryptophan, such as 15 to 60 millimoles, particularly 25 to 50 millimoles of tryptophan;

[0109] 190 to 270 millimoles of arginine (such as arginine hydrochloride or arginine glutamate), for example 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265 or 270 millimoles, particularly 200, 210, 225, 235, 250 or 260 millimoles;

[0110] 0.01 - 0.03% of a non-ionic surfactant, for example 0.01 - 0.03% by mass fraction (w / w), such as 0.02% by mass fraction (w / w);

[0111] A buffer (such as a histidine buffer); and

[0112] wherein the pH value of the preparation is in the range of 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, especially 6.4.

[0113] 91. A pharmaceutical preparation comprising an antibody or a binding fragment thereof for treatment according to any one of paragraphs 1 to 88, the preparation comprising 175 to 250 mg / ml of an anti-interleukin-13 receptor antibody or an antigen-binding fragment thereof, for example 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mg / ml, particularly 190, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, such as 200 mg / ml of an anti-interleukin-13 receptor antibody or an antigen-binding fragment thereof;

[0114] 5 to 100 millimoles of tryptophan (including 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 millimoles), for example 15 to 75 millimoles of tryptophan, such as 15 to 60 millimoles, especially 25 to 50 millimoles of tryptophan, for example 20 millimoles, 50 millimoles or 80 millimoles of tryptophan;

[0115] 140 to 290 millimoles of arginine (including 150 or 151 to 290 nM), for example 160 to 290 millimoles of arginine (such as arginine hydrochloride or arginine glutamate), for example 160, 165, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285 or 290 millimoles, especially 150, 185, 215, 225, 250, 260 or 280 millimoles of arginine;

[0116] 0.01 - 0.03% of a non-ionic surfactant (such as polysorbate), for example 0.01 - 0.03% mass fraction (w / w), such as 0.01%, 0.015%, 0.020%, 0.025% or 0.030%, especially 0.02% mass fraction of non-ionic surfactant;

[0117] A buffer (such as a histidine buffer), for example 15 to 55 millimoles of buffer (including 25 or 26 to 55 millimoles), such as 15, 20, 25, 30, 35, 40, 45, 50 or 55 millimoles of histidine buffer; especially 20, 35 or 50 millimoles of histidine buffer; and

[0118] The pH value of the preparation is in the range of 5.5 to 7.2 (including 5.5, 5.5, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, for example, 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, especially 5.8, 6.3, 6.4, 6.5, 6.6, 6.7 or 6.8).

[0119] 92. A method for treating a patient with sleep deprivation or sleep disorder, the method comprising administering an antibody or an antigen-binding fragment thereof (the antibody or antigen-binding fragment inhibits its signal transduction by binding to interleukin-13 receptor α1 (IL-13Rα1)), or a pharmaceutical preparation comprising the antibody or antigen-binding fragment, for example, as described in any one of paragraphs 1 to 88, treating by parenteral administration, the dose range for one treatment cycle being 200 mg to 600 mg (for example, 300, 400, 500 or 600 mg, such as 400 to 600 mg), for example, the treatment can reduce the sleep disorder (SD) score of the patient-oriented eczema assessment scale (POEM), for example, by 50% to 100% compared to the baseline, for example, by 2 to 4 points compared to the baseline.

[0120] 93. Use of an antibody or an antigen-binding fragment thereof (the antibody or antigen-binding fragment inhibits its signal transduction by binding to interleukin-13 receptor α1 (IL-13Rα1)) or a pharmaceutical preparation comprising the antibody or antigen-binding fragment (for example, as described in any one of paragraphs 1 to 88) in the preparation of a drug for treating sleep deprivation or sleep disorder in a patient, treating by parenteral administration, the dose range for one treatment cycle being 200 mg to 600 mg (for example, 300, 400, 500 or 600 mg, such as 400 to 600 mg), for example, the treatment can reduce the sleep disorder (SD) score of the patient-oriented eczema assessment scale (POEM), for example, by 50% to 100% compared to the baseline, for example, by 2 to 4 points compared to the baseline.

[0121] Surprisingly, the present inventors have confirmed that by administering an anti-IL13R antibody or antigen-binding fragment, such as ixekizumab, to a subject in need, the symptoms and severity of sleep deprivation or sleep disorder can be treated and / or improved.

[0122] In one embodiment, a method for treating a patient with sleep deprivation or sleep disorder is provided, the patient being a highly allergic patient as defined herein, using an antibody or its binding fragment or a pharmaceutical preparation as defined herein.

[0123] In one embodiment, there is provided an antibody or a binding fragment thereof as defined herein, or a pharmaceutical formulation, for use in the manufacture of a medicament for treating sleep deprivation or sleep disorder in a patient, such as a patient who is highly allergic.

[0124] In one embodiment, the improvement in sleep is not related to the improvement of an underlying disease (such as those disclosed herein) such as allergy.

[0125] In one embodiment, the improvement in sleep is related to the improvement of an underlying disease (such as those disclosed herein) such as allergy.

[0126] In one embodiment, treatment with ixekizumab can reduce the overall burden of the disease, such as reducing the overall burden of sleep deprivation or sleep disorder in a patient.

[0127] In one embodiment, treatment with ixekizumab can improve the quality of life of a patient with sleep deprivation or sleep disorder (such as a highly allergic patient).

[0128] In one embodiment, the patient has a type 2-driven inflammatory skin disease, such as a skin disease exacerbated by pro-inflammatory cytokines present in the skin. Thus, in one embodiment, ixekizumab is suitable for treating a patient with a type 2-driven inflammatory skin disease. In one embodiment, the type 2-driven inflammatory skin disease is atopic dermatitis (AD).

[0129] In one embodiment, the patient has pruritus. In one embodiment, the pro-inflammatory cytokines present in the patient's skin exacerbate the pruritus signaling in the patient's body, which may trigger an immune response, disrupt the skin barrier and drive the disease pathology. Thus, in one embodiment, ixekizumab can reduce or inhibit the pruritus signaling in the patient's body. In one embodiment, treatment with ixekizumab can prevent or reduce the disruption of the patient's skin barrier. In one embodiment, ixekizumab can reduce or inhibit the immune response that drives the disease pathology in a patient with pruritus.

[0130] Without wishing to be bound by theory, ixekizumab can inhibit the pruritus signaling pathway and / or inhibit the signaling of neuropathic pain (such as peripheral and / or central neuropathic pain, especially peripheral neuropathic pain), thereby improving sleep.

[0131] In one embodiment, the pro-inflammatory cytokine is interleukin-13, interleukin-4, or a combination of interleukin-13 and interleukin-4. In one embodiment, interleukin-13, interleukin-4, or both act as neuronal enhancers and amplify the itch signaling pathway through the 13Rα1 subunit of the type II receptor. Thus, in one embodiment, ixekizumab inhibits or attenuates neuronal enhancers that amplify the itch signaling pathway, such as interleukin-13 and / or interleukin-4.

[0132] In one embodiment, treatment with ixekizumab can reduce the itch neuronal response, for example, by the dual blockade of interleukin-4 and interleukin-13 by ixekizumab through the type II receptor.

[0133] Improving sleep has significant health benefits, including improving mood, enhancing concentration, reducing general inflammation markers in the body, increasing energy, reducing obesity, reducing the risk of heart disease, reducing the risk of diabetes, improving interpersonal relationships, enhancing self-esteem, improving the immune system, and enhancing the ability to cope with stress.

[0134] In one embodiment, combination therapy is employed, including the antibody, antigen-binding fragment, or formulation described in the present invention and another drug.

[0135] In one embodiment, the further drug is used to treat sleep insufficiency, such as hypnotic drugs, including but not limited to melatonin, zolpidem, zaleplon, eszopiclone, ramelteon, suvorexant, lemborexant, or doxepin. In one embodiment, the further drug is used to treat the symptoms of sleep insufficiency, such as narcolepsy. Examples of such drugs include but are not limited to stimulants or wake-promoting drugs, such as modafinil, armodafinil, pitolisant, or solriamfetol.

[0136] Surprisingly, according to the present disclosure, the improvement of the disease after treatment with an anti-IL-13Rα1 antibody or its antigen-binding fragment is closely related to the reduction of thymus and activation-regulated chemokine (TARC). In fact, the reduction of TARC is closely related to the reduction of the eczema area and severity index (EASI).

[0137] In one embodiment, the patient has a skin disease, such as selected from the following group of diseases: dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis, or seborrheic dermatitis; eczema; hand, foot, and mouth disease; urticaria (including urticaria associated with lupus), psoriasis, infectious diseases, such as fungal infection or bacterial infection, such as impetigo or folliculitis; allergic skin reactions; Ehlers-Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE).

[0138] In one embodiment, the patient has dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis. In one embodiment, the patient has atopic dermatitis (AD), such as moderate to severe atopic dermatitis. In one embodiment, the patient has eczema. In one embodiment, the patient's sleep deprivation or sleep disorder is caused by their eczema. In one embodiment, the patient has urticaria. In one embodiment, the patient has Ehlers-Danlos syndrome (EDS), asthma or angioedema (such as hereditary angioedema (HAE)). In one embodiment, the patient has Ehlers-Danlos syndrome. In one embodiment, the patient has asthma. In one embodiment, the patient has angioedema, such as hereditary angioedema (HAE).

[0139] The inventors of the present invention have also confirmed that the antibodies, antigen-binding fragments and compositions of the present invention can be used to treat other diseases with allergic components, such as allergic epithelial diseases, such as allergic asthma and eosinophilic esophagitis.

[0140] Thus, in a separate aspect, there is provided a method of treating an allergic disease (such as a disease with elevated IgE levels (elevated relative to normal levels)), the method using an antibody, a binding fragment thereof or a composition comprising them, the antibody inhibiting its signal transduction by binding to interleukin-13 receptor α1, such as as described elsewhere herein (for atopic dermatitis).

[0141] Although not wishing to be bound by theory, the inventors believe that these allergic diseases and the cytokines and mechanisms operative in this atopic dermatitis population are the same, similar or related.

[0142] In one embodiment, the allergic disease manifests in epithelial tissue.

[0143] In one embodiment, the allergic disease is allergic asthma, such as poorly controlled and / or moderate to severe asthma. In one embodiment, the allergic disease is eosinophilic esophagitis, such as poorly controlled and / or moderate to severe eosinophilic esophagitis.

[0144] In one embodiment, the treatment method of the present invention is applied to patients with acute allergic reactions.

[0145] In one embodiment, the patient is identified as allergic before treatment, such as when determined at baseline and at a level of at least 10,000 KU / L ± 2,000.

[0146] The preferences described herein for atopic dermatitis, such as dosage, etc. are equally applicable to the allergic disease indication.

[0147] In one embodiment, the allergic disease is not atopic dermatitis. In one embodiment, the allergic disease is not eosinophilic esophagitis. In one embodiment, the allergic disease is not psoriasis.

[0148] Detailed Description

[0149] As used herein, sleep loss, sleep deprivation, or sleep disorder refers to the inability to fall asleep or difficulty in maintaining sleep, for example, due to disruption of the sleep-wake cycle. In one embodiment, the patient wakes up one or more times at night, for example, waking up 1, 2, 3, 4, 5 times or more times per night on average. In one embodiment, the patient requires at least 45 minutes on average to fall asleep, for example, 1, 1.5, 2 hours to fall asleep. In one embodiment, the patient is awake at night for at least 30 minutes on average (such as 1, 1.5, 2 hours or longer), for example, occurring 3 times per week. In one embodiment, the patient wakes up one or more times at night, for example, waking up 1, 2, 3, 4, 5 times or more times per night on average, and requires at least 45 minutes on average to fall asleep, for example, 1, 1.5, 2 hours to fall asleep. In one embodiment, the patient wakes up one or more times at night, for example, waking up 1, 2, 3, 4, 5 times or more times per night on average, and is awake at night for at least 30 minutes on average (such as 1, 1.5, 2 hours or longer), for example, occurring 3 times per week. In one embodiment, the patient requires at least 45 minutes on average to fall asleep, for example, 1, 1.5, 2 hours to fall asleep, and is awake at night for at least 30 minutes on average (such as 1, 1.5, 2 hours or longer), for example, occurring 3 times per week. In one embodiment, the patient wakes up one or more times at night, for example, waking up 1, 2, 3, 4, 5 times or more times per night on average, requires at least 45 minutes on average to fall asleep, for example, 1, 1.5, 2 hours to fall asleep, and is awake at night for at least 30 minutes on average (such as 1, 1.5, 2 hours or longer), for example, occurring 3 times per week.

[0150] The Patient-Oriented Eczema Measure (POEM) used herein is a 7-item questionnaire for patients that assesses the occurrence of disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding, and oozing) in the patient last week through a scoring system from 0 (no days) to 4 (every day). The total score ranges from 0 to 28 points, and the higher the score, the more severe the eczema symptoms.

[0151] The sleep disturbance (SD) score used in this article refers to the score of the questions related to sleep disturbance in the Patient-Oriented Eczema Measure (POEM) questionnaire. The score ranges from 0 (no days with sleep disturbance) to 4 (sleep disturbance every day). The relevant questions are usually phrased as follows: In the past week, on how many nights was your sleep disturbed by eczema? The available answers are, for example: no days (SD score of 0), 1 - 2 days (SD score of 1), 3 - 4 days (SD score of 2), 5 - 6 days (SD score of 3), or every day (SD score of 4).

[0152] SCORAD used in this article refers to a clinical tool for assessing the extent and severity of atopic dermatitis (Atopic Dermatitis Severity Index). In the context of the present invention, SCORAD is a scoring tool that can be used as an alternative to the Patient-Oriented Eczema Measure (POEM).

[0153] To calculate the Atopic Dermatitis Severity Index (SCORAD), first determine the extent of disease involvement using the nine-point method to estimate the percentage of the body surface area affected. The maximum value of the extent of disease involvement is 100%. Next, calculate the disease severity based on six features: erythema, edema, exudation / crusting, excoriation, lichenification, and dryness. The score for each feature ranges from 0 to 3, with 0 indicating the absence of the feature and 3 indicating severe. The scores for each feature are added together, and the total severity score is at most 18 points. Subjective symptoms, including sleep loss and pruritus, are measured using a 10-cm visual analogue scale, with a maximum total score of 20 points. Finally, the SCORAD index is calculated by the following formula: extent of involvement / 5 + 7 × severity / 2 + subjective symptom score.

[0154] The sleep deprivation part in the Atopic Dermatitis Severity Index (SCORAD) used in this article refers to the score of the sleep loss question in SCORAD. This score reflects the average situation of the patient in the past 3 days or nights, ranging from 0 (no sleep loss) to 10 (the most severe sleep loss imaginable).

[0155] The Sleep Disturbance Numerical Rating Scale (SD NRS) used in this article is a single-item patient-reported outcome (PRO) measure for quantifying sleep disturbance / sleep loss. The SD NRS asks the patient to rate the sleep loss situation of the previous night according to a rating scale from 0 (“no sleep loss”) to 10 (“didn't sleep at all”).

[0156] In one embodiment, the reduction in the sleep disorder score (SD score) during or after treatment compared to the baseline ranges from -50% to -100%, for example, a reduction of -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -55% to -100%, for example, a reduction of -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -60% to -100%, for example, a reduction of -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -65% to -100%, for example, a reduction of -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -70% to -100%, for example, a reduction of -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -75% to -100%, for example, a reduction of -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -80% to -100%, for example, a reduction of -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -85% to -100%, for example, a reduction of -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -90% to -100%, for example, a reduction of -90%, -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -95% to -100%, for example, a reduction of -95% or -100%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -15% to -25%, for example, a reduction of -15%, -16%, -17%, -18%, -19%, -20%, -21%, -22%, -23%, -24% or -25%.In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -25% to -35%, such as a reduction of -25%, -26%, -27%, -28%, -29%, -30%, -31%, -32%, -33%, -34%, or -35%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from -35% to -45%, such as a reduction of -35%, -36%, -37%, -38%, -39%, -40%, -41%, -42%, -43%, -44%, or -45%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 45% to -55%, such as a reduction of -45%, -46%, -47%, -48%, -49%, -50%, -51%, -52%, -53%, -54%, or -55%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 55% to -65%, such as a reduction of -55%, -56%, -57%, -58%, -59%, -60%, -61%, -62%, -63%, -64%, or -65%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 65% to -75%, such as a reduction of -65%, -66%, -67%, -68%, -69%, -70%, -71%, -72%, -73%, -74%, or -75%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 75% to -85%, such as a reduction of -75%, -76%, -77%, -78%, -79%, -80%, -81%, -82%, -83%, -84%, or -85%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 85% to -95%, such as a reduction of -85%, -86%, -87%, -88%, -89%, -90%, -91%, -92%, -93%, -94%, or -95%. In one embodiment, the reduction in the SD score during or after treatment compared to the baseline ranges from 95% to -100%, such as a reduction of -95%, -96%, -97%, -98%, -99%, or -100%.

[0157] In one embodiment, the sleep disorder (SD) score during or after treatment is reduced by 1 to 4 points relative to the baseline, such as 1, 2, 3, or 4 points. In one embodiment, the sleep disorder (SD) score during or after treatment is reduced by 2 or more points relative to the baseline, such as 2, 3, or 4 points. In one embodiment, the sleep disorder (SD) score during or after treatment is reduced by 3 or more points relative to the baseline, such as 3 or 4 points.

[0158] In one embodiment, the reduction in the sleep deprivation component of the SCORAD (SCORing Atopic Dermatitis) during or after treatment, compared to baseline, is between -20% and -100%, such as a reduction of –20%, -25%, -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -30% and -100%, such as a reduction of -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -40% and -100%, such as a reduction of -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep loss or sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -50% and -100%, such as a reduction of -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -60% and -100%, such as a reduction of -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -70% and -100%, such as a reduction of -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -80% and -100%, such as a reduction of -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -20% and -70%, such as a reduction of -20%, -25%, -30%, -35%, -40%, -50%, -55%, -60%, -65% or -70%. In one embodiment, the reduction in the sleep deprivation component of the SCORAD during or after treatment, compared to baseline, is between -30% and -60%, such as a reduction of -30%, -35%, -40%, -50%, -55% or -60%.In one embodiment, during or after treatment, the reduction in the sleep deprivation component of SCORAD relative to baseline is between -35% and -55%, such as a reduction of -35%, -40%, -50%, or -55%.

[0159] In one embodiment, the sleep deprivation component of the Severity Scoring of Atopic Dermatitis (SCORAD) is reduced by 1 to 10 points relative to baseline, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation component of SCORAD is reduced by 2 points or more relative to baseline, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 3 points or more relative to baseline, such as 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 4 points or more relative to baseline, such as 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 5 points or more relative to baseline, such as 5, 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 6 points or more relative to baseline, such as 6, 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 7 points or more relative to baseline, such as 7, 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 8 points or more relative to baseline, such as 8, 9, or 10 points. In one embodiment, the sleep deprivation of SCORAD is reduced by 9 points or more relative to baseline, such as 9 or 10 points.

[0160] In one embodiment, the reduction in the Sleep Disturbance Numerical Rating Scale (SD NRS) during or after treatment compared to baseline ranges from -20% to -100%, for example, a reduction of -20%, -25%, -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -30% to -100%, for example, a reduction of -30%, -35%, -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -40% to -100%, for example, a reduction of -40%, -45%, -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -50% to -100%, for example, a reduction of -50%, -55%, -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -60% to -100%, for example, a reduction of -60%, -65%, -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -70% to -100%, for example, a reduction of -70%, -75%, -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -80% to -100%, for example, a reduction of -80%, -85%, -90%, -95% or -100%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -20% to -70%, for example, a reduction of -20%, -25%, -30%, -35%, -40%, -50%, -55%, -60%, -65% or -70%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -30% to -60%, for example, a reduction of -30%, -35%, -40%, -50%, -55% or -60%. In one embodiment, the reduction in the SD NRS during or after treatment compared to baseline ranges from -35% to -55%, for example, a reduction of -35%, -40%, -50% or -55%.

[0161] In one embodiment, the Sleep Disturbance Numerical Rating Scale (SD NRS) is reduced by 1 to 10 points, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 2 points or more, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 3 points or more, such as 3, 4, 5, 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 4 points or more, such as 4, 5, 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 5 points or more, such as 5, 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 6 points or more, such as 6, 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 7 points or more, such as 7, 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 8 points or more, such as 8, 9, or 10 points, compared to the baseline. In one embodiment, the SD NRS is reduced by 9 points or more, such as 9 or 10 points, compared to the baseline.

[0162] In one embodiment, the patient's baseline SD score is at least 1, such as 1, 2, 3, or 4. In one embodiment, the patient's baseline SD score is at least 2, such as 2, 3, or 4. In one embodiment, the patient's baseline SD score is at least 3, such as 3 or 4. In one embodiment, the patient's baseline SD score is 4.

[0163] In one embodiment, the baseline sleep deprivation component of the patient's SCORAD (SCORing Atopic Dermatitis) is at least 1 point, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 2 points, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 3 points, such as 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 4 points, such as 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 5 points, such as 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 6 points, such as 6, 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 7 points, such as 7, 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 8 points, such as 8, 9, or 10 points. In one embodiment, the baseline sleep deprivation component of the patient's SCORAD is at least 9 points, such as 9 or 10 points.

[0164] In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 1 point, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 2 points, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 3 points, such as 3, 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 4 points, such as 4, 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 5 points, such as 5, 6, 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 6 points, such as 6, 7, 8, 9, or 10 points. In one embodiment, the score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 7 points, such as 7, 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 8 points, such as 8, 9, or 10 points. In one embodiment, the baseline score of the patient's Sleep Disorder Numerical Rating Scale (SD NRS) is at least 9 points, such as 9 or 10 points.

[0165] As used herein, disease improvement refers to an improvement in the disease state, such as measured by a clinically relevant score, particularly a reduction in the sleep disorder score of the Patient-Oriented Eczema Measure (POEM). Thus, in one embodiment, disease improvement refers to a reduction in the sleep disorder score of the POEM. In another embodiment, disease improvement refers to a reduction in the sleep deprivation component of the Severity Scoring of Atopic Dermatitis (SCORAD). In another embodiment, disease improvement refers to a reduction in the Sleep Disorder Numerical Rating Scale (SD NRS).

[0166] A clinically relevant score is a score used clinically, such as a score used by a doctor.

[0167] As used herein, "Pruritus" or "pruritis" refers to the condition of itchy skin. This causes a very uncomfortable and irritable feeling, prompting people to scratch the skin. Pruritus can be caused by a variety of different conditions, including skin diseases (such as atopic dermatitis and psoriasis), internal diseases (such as liver and kidney diseases, lymphoma), neurological disorders (such as multiple sclerosis), mental diseases (such as anxiety and obsessive-compulsive disorder), and allergic reactions.

[0168] The Pruritus Numerical Rating Scale (P-NRS) used herein is the score that a patient assigns to evaluate the intensity of pruritus within the past 24 hours. The score ranges from 0 to 10, where a score of 0 indicates "no pruritus" and the highest score of 10 indicates "the most severe pruritus imaginable". The Mean Pruritus Numerical Rating Scale (Mean P-NRS) used herein refers to the score that a patient assigns to evaluate the average intensity of pruritus within the past 24 hours. The score ranges from 0 to 10, where a score of 0 indicates "no pruritus" and the highest score of 10 indicates "the most severe pruritus imaginable". The Peak Pruritus Numerical Rating Scale (Peak P-NRS) or the Worst Pruritus Numerical Rating Scale (Worst P-NRS) used herein refers to the score that a patient assigns to evaluate the worst intensity of pruritus within the past 24 hours. The score ranges from 0 to 10, where a score of 0 indicates "no pruritus" and the highest score of 10 indicates "the most severe pruritus imaginable".

[0169] In one embodiment, the disease is improved by a reduction of -20% to -100% in the Eczema Area and Severity Index (EASI) score compared to baseline, such as a 50% reduction in EASI, a 75% reduction in EASI, or a 90% reduction in EASI. The EASI score and EASI are used interchangeably herein.

[0170] The Eczema Area and Severity Index (EASI) score used herein is a tool for measuring the area (indicating the extent of the disease) and severity of atopic eczema. The number following "EASI" represents the percentage reduction in the score compared to the baseline score. Thus, for example, EASI 50 refers to a 50% reduction in the score, and EASI 90 refers to a 90% reduction in the score.

[0171] In one embodiment, the degree of disease improvement is measured by a reduction in the Investigator's Global Assessment (IGA).

[0172] In one embodiment, according to the treatment regimen of the present invention, the Investigator's Global Assessment (IGA) score decreases during or after treatment, for example, the score is 0, 1, or 2 (corresponding to no signs of inflammation, almost no signs of inflammation, and mild disease, respectively). In particular, the cases where the IGA score is 0 or 1 are provided.

[0173] The Investigator's Global Assessment (IGA) used herein is a tool for evaluating atopic dermatitis. It uses a scoring system of 0 - 5 based on the severity of the patient's symptoms:

[0174] Score Severity Symptom description 0 None No sign of inflammation 1 Virtually none Just perceptible erythema and just perceptible papules / infiltration 2 Mild disease Mild erythema and mild papules / infiltration 3 Moderate disease Moderate erythema and moderate papules / infiltration 4 Severe disease Severe erythema and severe papules / infiltration 5 Very severe disease Severe erythema and severe papules / infiltration with exudation / crusting

[0175] In a separate aspect, there is provided the use of the antibodies, antigen-binding fragments, or pharmaceutical formulations disclosed herein for treating or improving food allergy reactions, particularly severe food allergy reactions such as peanut allergy.

[0176] In one embodiment, the baseline immunoglobulin E (IgE) level of a highly allergic patient has been determined and is at least 10,000 KU / L ± 2,000 KU / L, such as 8000, 8500, 9000, 9500, 10000, 10500, 11000, 11500 or 12000 KU / L.

[0177] In one embodiment, before treatment, the patient is identified as a highly allergic patient. For example, the baseline immunoglobulin E (IgE) level of the patient has been determined and is at least 10,000 KU / L ± 2,000 KU / L. Thus, in one embodiment, before administering the antibody or its binding fragment, pharmaceutical formulation or drug as defined herein, the patient is identified as a highly allergic patient, whose baseline IgE level has been determined and is at least 10,000 KU / L ± 2,000 KU / L. Accordingly, in one embodiment, the target population to be treated is those highly allergic patients whose baseline IgE levels have been determined and are at least 10,000 KU / L ± 2,000 KU / L.

[0178] In one embodiment, it is determined that the patient is highly allergic through clinical observation.

[0179] As used herein, "poorly controlled" means that the control effect is poor through existing approved drugs (such as topical drugs and / or dupilumab). The results show that ixekizumab has comparable efficacy to dupilumab and even higher efficacy in some cases, thus demonstrating the potential of ixekizumab as an alternative therapy for treating and controlling sleep insufficiency.

[0180] Therefore, in one embodiment, a treatment regimen for a class of patient groups is provided. These patients have poor symptom control and / or adverse reactions when treated with dupilumab, that is to say, the treatment effect of this class of patient groups with dupilumab is not ideal. Accordingly, in one embodiment, the patient has previously received treatment with dupilumab. In one embodiment, the patient has sleep deprivation or sleep disorder and is poorly controlled when treated with dupilumab. In one embodiment, the patient has atopic dermatitis and is poorly controlled when treated with dupilumab. In one embodiment, the patient has atopic dermatitis and at the same time has sleep deprivation or sleep disorder and is poorly controlled when treated with dupilumab.

[0181] As used herein, asthma is a respiratory disease characterized by inflammation and bronchospasm, in which the muscles around the airways tighten and contract in an attempt to keep the airways open. This causes the patient to experience coughing, wheezing, chest tightness and shortness of breath. When the breathing problem becomes severe, this is usually referred to as an asthma attack. Typical asthma may present as a dry cough or a feeling of obstruction in the throat.

[0182] The allergic asthma (which can be used interchangeably with allergy-induced asthma) referred to in this article is a form of asthma. After inhaling allergens, the lungs of patients become inflamed and the airways constrict. Common allergens include pollen, dust, animal dander, and mold. Patients with allergic asthma have many of the same symptoms as those with non-allergic asthma, such as coughing, wheezing, chest tightness, and shortness of breath. Therefore, the main difference between these two conditions is that patients with allergic asthma usually experience symptoms after inhaling allergens.

[0183] The eosinophilic esophagitis (EOE) referred to in this article is a chronic immune system disease in which eosinophils accumulate in the esophagus (where eosinophils do not normally exist). This accumulation is a reaction to food, allergens, or acid reflux and can cause inflammation and damage to the esophageal tissue. This can in turn lead to esophageal stricture and difficulty swallowing. In severe cases, it may even trigger a medical emergency due to food getting stuck in the throat. Most patients with eosinophilic esophagitis have atopic diseases. Therefore, individuals with atopic dermatitis, food allergies, or other environmental allergies are at a higher risk of developing eosinophilic esophagitis. A family history of eosinophilic esophagitis is also a risk factor for this disease. Currently, the US Food and Drug Administration (US FDA) has not approved any drugs for the treatment of eosinophilic esophagitis. However, proton pump inhibitors (PPIs) have been shown to reduce esophageal inflammation in some patients with eosinophilic esophagitis and are therefore often used as first-line treatment drugs. Corticosteroids can also be used to help control inflammation.

[0184] The atopic dermatitis (AD) used in this article refers to skin inflammation, including: dry / itchy skin and red rashes. Atopic dermatitis can be a very painful, frustrating, and psychologically damaging disease. The most common side effect of atopic dermatitis is itching, and active atopic dermatitis cannot be diagnosed without a history of itching. In fact, patients with atopic dermatitis often complain that itching is the most annoying and intolerable symptom they have to cope with.

[0185] The psoriasis used in this article refers to a skin disease that causes skin cells to proliferate much faster than normal. This leads to the appearance of red, itchy, scaly patches, which usually appear on the scalp, knees, elbows, and trunk. There are different types of psoriasis, including pustular psoriasis, guttate psoriasis, inverse psoriasis, and erythrodermic psoriasis. Most types of psoriasis go through periodic episodes that last for weeks or months and then remit for a period of time, or even enter a remission phase.

[0186] As used herein, angioedema refers to the rapid onset of edema (swelling) in the skin or subcutaneous area due to the accumulation of fluid, usually in response to an allergic trigger. Angioedema can affect different parts of the body but is commonly manifested in the eyes, lips, genitals, hands, and feet. Angioedema can occur concomitantly with urticaria or alone. In more severe cases, angioedema can lead to difficulty breathing, abdominal pain, and dizziness.

[0187] As used herein, Ehlers-Danlos syndrome (EDS) refers to a group of genetic disorders in which connective tissues such as tendons, ligaments, blood vessels, etc. are affected. There are 13 types of Ehlers-Danlos syndrome, including hypermobile Ehlers-Danlos syndrome (the most common), classical Ehlers-Danlos syndrome, vascular Ehlers-Danlos syndrome, and kyphoscoliotic Ehlers-Danlos syndrome. Different types of Ehlers-Danlos syndrome have some common symptoms such as increased joint range of motion (hypermobility), and highly elastic and fragile skin. There is currently no known cure for Ehlers-Danlos syndrome, and treatment is mainly supportive, such as physical therapy.

[0188] As used herein, urticaria refers to the sudden appearance of itchy, pale red papules or wheals on the skin. There are several types of urticaria, including acute urticaria (lasting less than 6 weeks, usually caused by food, drugs, or infections), chronic urticaria (lasting more than 6 weeks), and physical urticaria (caused by factors that irritate the skin, such as cold, heat, pressure, sweating, etc.). In one embodiment, the treatment method of the present invention is used to treat acute urticaria.

[0189] As used herein, interleukin-13 receptor (IL-13R) is a type I cytokine receptor that can bind to interleukin-13. It consists of two subunits encoded by IL13Rα1 and IL4R respectively. These two genes encode the proteins IL-13Rα1 and IL-4Rα respectively. They form a dimer, with IL-13 binding to the IL-13Rα1 chain and IL-4Rα stabilizing this interaction. Due to the presence of the IL4R subunit, IL13R can also initiate IL-4 signal transduction. In both cases, signal transduction is achieved by activating the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, ultimately leading to STAT6 phosphorylation. The UniProt number of human IL-13Rα1 is P3597.

[0190] IL-13Rα2, previously known as IL-13R and IL-13Rα, is another receptor that can bind to IL-13. However, in contrast to IL-13Rα1, this protein binds to IL-13 with high affinity but does not bind IL-4. The UniProt number of human IL-13Rα2 is Q14627.

[0191] In one embodiment, the anti-interleukin-13 receptor antibody or binding fragment thereof of the present invention binds to interleukin-13 receptor α1. In one embodiment, the antibody or binding fragment binds only to interleukin-13 receptor α1 and not to interleukin-13 receptor α2.

[0192] In one embodiment, CDRH1 is an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1).

[0193] In one embodiment, CDRH2 is an amino acid sequence VIYPGDSYTR (SEQ ID NO: 2)

[0194] In one embodiment, CDRH3 has the following formula:

[0195] SEQ ID NO: 3X 1 Pro Asn Trp Gly X 6 X 7 Asp X 9

[0196] X 1 represents phenylalanine (Phe), methionine (Met),

[0197] glutamine (Gln), leucine (Leu) or valine

[0198] (Val)

[0199] X 6 represents serine (Ser) or alanine (Ala).

[0200] X 7 represents phenylalanine (Phe), leucine (Leu), ala

[0201] nine (Ala) or methionine (Met).

[0202] X 9 represents tyrosine (Tyr), glutamine (Gln), lys

[0203] ine (Lys), arginine (Arg), tryptophan

[0204] (Trp), histidine (His), alanine (Ala), thr

[0205] eonine (Thr), serine (Ser), asparagine

[0206] (Asn) or glycine (Gly).

[0207] In one embodiment, the anti-interleukin-13 receptor (IL-13R) antibody or binding fragment used in the preparation of the present invention comprises a complementarity-determining region heavy chain 3 (CDRH3) independently selected from the sequences consisting of SEQ ID NO: 4 to 30.

[0208] In one embodiment, the anti-interleukin-13 receptor (IL13R) antibody or binding fragment used in the present invention comprises a variable heavy chain complementarity-determining region 1 (VH CDR1) having the amino acid sequence as shown in SEQ ID NO: 1; a variable heavy chain complementarity-determining region 2 (VH CDR2) having the amino acid sequence as shown in SEQ ID NO: 2; and a variable heavy chain complementarity-determining region 3 (VH CDR3) having the amino acid sequence as shown in SEQ ID NO: or 3 (there may be an error in the original text here).

[0209] In one embodiment, the anti-interleukin-13 receptor (IL13R) antibody or binding fragment used in the present invention comprises a complementarity-determining region heavy chain 1 (CDRH1) having the amino acid sequence as shown in Sequence No. 1; a complementarity-determining region heavy chain 2 (CDRH2) having the amino acid sequence as shown in Sequence No. 2; and a complementarity-determining region heavy chain 3 (CDRH3) having the amino acid sequence as shown in Sequence No. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0210] In one embodiment, the anti-interleukin-13 receptor (IL-13R) antibody or binding fragment used in the present invention comprises a complementarity-determining region heavy chain 3 (CDRH3) having the amino acid sequence MPNWGSLDH (SEQ ID NO: 10).

[0211] In one embodiment, the anti-IL13R antibody or binding fragment used in the present invention comprises a CDRH1 having the amino acid sequence shown in SEQID NO: 1, a CDRH2 having the amino acid sequence shown in SEQ ID NO: 2, and a CDRH3 having the amino acid sequence shown in SEQ ID NO: 10.

[0212] In one embodiment, CDRL1 is an amino acid sequence RASQSISSSYLA (SEQ ID NO: 31).

[0213] In one embodiment, CDRL2 is an amino acid sequence GASSRAT SEQ ID NO: 32.

[0214] In one embodiment, CDL3 has the following molecular formula:

[0215] SEQ ID NO:33 Gln X 2 X 3 X 4 X 5

[0216] X 2 represents glutamine (Gln), arginine (Arg), methionine

[0217] (Met), serine (Ser), threonine (Thr), or

[0218] valine (Val).

[0219] X 3 represents tyrosine (Tyr) or valine (Val).

[0220] X 4 represents glutamic acid (Glu), alanine (Ala), glycine

[0221] (Gly), or serine (Ser).

[0222] X 5 represents threonine (Thr), alanine (Ala), or serine

[0223] (Ser).

[0224] In one embodiment, the interleukin-13 receptor α1 (IL-13Rα1) antibody used in the preparation of the present invention comprises a complementarity-determining region light chain 3 (CDRL3) independently selected from the sequences consisting of SEQ ID NOs: 34 to 47.

[0225] In one embodiment, the anti-interleukin-13 receptor (IL-13R) antibody or binding fragment used in the present invention comprises a complementarity-determining region light chain 3 (CDL3) having the amino acid sequence QQYAS (SEQ ID NO: 45).

[0226] In one embodiment, the anti-IL13R antibody of the present invention comprises a CDRL1 having the amino acid sequence shown in SEQ ID NO: 31, a CDRL2 having the amino acid sequence shown in SEQ ID NO: 32, and a CDRL3 having the amino acid sequence shown in SEQ ID NO: 45.

[0227] In one embodiment, the interleukin-13 receptor (IL-13R) antibody used in the present invention comprises a complementarity-determining region light chain 3 (CDRL3) independently selected from the sequences consisting of SEQ ID NOs: 34 to 47.

[0228] In one embodiment, CDRL3 comprises the amino acid sequence as set forth in SEQ ID NO: 33.

[0229] In one embodiment, the VH region is independently selected from the sequences consisting of the following sequences: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51, and sequences having at least 95% identity to any of the above sequences.

[0230] SEQ ID NO: 51

[0231] Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Val Ile Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Met Pro Asn Trp Gly Ser Leu Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

[0232] In one embodiment, VL is independently selected from the sequences consisting of SEQ ID NO: 52, SEQ ID NO: 53, and SEQ ID NO: 54, and sequences having at least 95% identity to any of the above sequences (*K is deleted in post-translational modification).

[0233] SEQ ID NO: 53

[0234] EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEI*

[0235] In one embodiment, the heavy chain variable region (VH) sequence is SEQ ID NO:48 (or a sequence that is at least 95% identical thereto), and the light chain variable region (VL) sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VH sequence is SEQ ID NO:49 (or a sequence that is at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VH sequence is SEQ ID NO:50 (or a sequence that is at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence that is at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VL sequence is SEQ ID NO:52 (or a sequence that is at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VL sequence is SEQ ID NO:53 (or a sequence that is at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the VL sequence is SEQ ID NO:54 (or a sequence that is at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence that is at least 95% identical to any of the foregoing).

[0236] In one embodiment, the heavy chain variable region (VH) sequence is SEQ ID NO: 51 (or a sequence that is at least 95% identical thereto), and the light chain variable region (VL) sequence is SEQ ID NO: 53 (or a sequence that is at least 95% identical thereto).

[0237] As used herein, the variable region refers to the region of an antibody chain that contains the complementarity determining regions (CDRs) and an appropriate framework.

[0238] In one embodiment, the heavy chain comprises a sequence independently selected from the group consisting of SEQ ID NOs: 55, 56, 57, 58, 59, and 60 (or a sequence having at least 95% identity to any one of the foregoing sequences), and the light chain is independently selected from the group consisting of SEQ ID NOs: 61, 62, and 63 (or a sequence having at least 95% identity to any one of the foregoing sequences).

[0239] In one embodiment, the light chain is independently selected from the following group of sequences: SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, and a sequence that is at least 95% identical to any one of the foregoing sequences.

[0240] In one embodiment, the heavy chain is independently selected from SEQ ID NOs: 55, 56, 57, 58, 59, and 60 (or a sequence that is at least 95% identical to any one of the foregoing sequences), and the light chain is independently selected from SEQ ID NOs: 61, 62, and 63 (or a sequence that is at least 95% identical to any one of the foregoing sequences).

[0241] In one embodiment, the heavy chain is SEQ ID NO:55 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:61, 62, or 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:56 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:61, 62, or 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:57 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:62 or 63 and 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:58 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:61, 62, and 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:59 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:61, 62, and 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:60 (or a sequence that is at least 95% identical thereto), and the light chain is independently selected from SEQ ID NO:61, 61, and 63 (or a sequence that is at least 95% identical to any of the foregoing). In one embodiment, the heavy chain is SEQ ID NO:58 or 60 (or any one of the sequences that is at least 95% identical thereto), and the light chain has the sequence shown in SEQ ID NO:61 (or a sequence that is at least 95% identical thereto). In one embodiment, the heavy chain is SEQ ID NO:58 (or any one of the sequences that is at least 95% identical thereto), and the light chain has the sequence shown in SEQ ID NO:61 (or a sequence that is at least 95% identical thereto). In one embodiment, the heavy chain is SEQ ID NO:60 (or any one of the sequences that is at least 95% identical thereto), and the light chain has the sequence shown in SEQ ID NO:61 (or a sequence that is at least 95% identical thereto).

[0242] In one embodiment, the anti-interleukin-13 receptor antibody of the present invention comprises a complementarity determining region heavy chain 1 (CDRH1) having the amino acid sequence shown in SEQ ID NO: 1, a complementarity determining region heavy chain 2 (CDRH2) having the amino acid sequence shown in SEQ ID NO: 2, a complementarity determining region heavy chain 3 (CDRH3) having the amino acid sequence shown in SEQ ID NO: 10, a complementarity determining region light chain 1 (CDRL1) having the amino acid sequence shown in SEQ ID NO: 31, a complementarity determining region light chain 2 (CDRL2) having the amino acid sequence shown in SEQ ID NO: 32, and a complementarity determining region light chain 3 (CDRL3) having the amino acid sequence shown in SEQ ID NO: 45.

[0243] In one embodiment, the anti-interleukin-13 receptor antibody is ixekizumab (formerly known as ASLAN004).

[0244] As used herein, "derived from" means that the sequence used or a sequence highly similar to the sequence used is obtained from the original genetic material (such as the light or heavy chain of an antibody).

[0245] As used herein, "at least 95% identical" is intended to refer to an amino acid sequence that has 95% or higher identity over its full length to a reference sequence, such as 96%, 97%, 98% or 99% identical. Software programs can be used to calculate the percentage of identity.

[0246] Any discussion herein of any protein, antibody or amino acid sequence will be understood to include any variants of that protein, antibody or amino acid sequence that arise during manufacture and / or storage. For example, during manufacture or storage, an antibody may undergo deamidation (e.g., at asparagine or glutamine residues), and / or glycosylation may change, and / or a glutamine residue may be converted to pyroglutamic acid, and / or N-terminal or C-terminal residues may be removed or "trimmed" (during manufacture, the C-terminal lysine residue encoding the antibody is often removed), and / or part or all of the signal sequence may not be fully processed and thus remains at the end of the antibody. It should be understood that an antibody or its binding fragment containing a specific amino acid sequence may be a heterogeneous mixture of the stated or encoded sequence and variants of the stated or encoded sequence or its binding fragment.

[0247] In one embodiment, the present invention encompasses sequences in which the C-terminal lysine disclosed herein has been cleaved.

[0248] In one embodiment, the antibody or its binding fragment used in the formulations of the present invention is humanized. As used herein, humanization (including complementarity-determining region grafted antibodies) refers to a molecule having one or more complementarity-determining regions (CDRs) from a non-human species and framework regions from human immunoglobulin molecules (see, e.g., U.S. Patent 5,585,089; International Publication WO91 / 09967). It should be understood that it may only be necessary to transfer the specificity-determining residues in the CDRs rather than the entire CDRs (see, e.g., the article by Kashmiri et al. in Methods, Vol. 36, pp. 25-34, 2005). The humanized antibody may optionally further comprise one or more framework residues from the non-human species providing the CDRs. For a review, see the article by Vaughan et al. in Nature Biotechnology, Vol. 16, pp. 535-539, 1998).

[0249] When grafting complementarity-determining regions (CDRs) or specificity-determining residues, any suitable receptor variable region framework sequence can be used depending on the class / type of the donor antibody from which the CDRs are derived, including framework regions from mice, primates, and humans. Examples of human framework regions that can be used in the present invention include KOL, NEWM, REI, EU, TUR, TEI, LAY, and POM (Kabat et al.). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain, and EU, LAY, and POM can be used for both the heavy and light chains. Alternatively, human germline sequences can also be used; these sequences can be obtained from: http: / / vbase.mrc-cpe.cam.ac.uk /

[0250] In the humanized antibodies used in the present invention, the receptor heavy and light chains do not necessarily need to be derived from the same antibody and, if desired, may comprise composite chains having framework regions from different chains.

[0251] The sequence of the framework region does not have to be identical to that of the receptor antibody. For example, uncommon residues can be changed to more common residues in that receptor chain class or type. Alternatively, selected residues in the receptor framework region can also be changed to correspond to the residues at the same position in the donor antibody (see Reichmann et al., Nature, Vol. 332, pp. 323-324, 1998). Such changes should be kept to a minimum required to restore the affinity of the donor antibody. A protocol for selecting residues in the receptor framework region that may need to be changed is set forth in WO91 / 09967.

[0252] In one embodiment, the anti-interleukin 13 receptor (IL13R) antibody of the present invention is fully human, particularly one or more variable domains are fully human. A fully human molecule means that the variable regions of the heavy and light chains and (if present) the constant regions are derived from humans or are substantially identical to sequences of human origin, not necessarily from the same antibody. Examples of fully human antibodies may include, for example, antibodies produced by the phage display methods described above, as well as antibodies produced in mice in which the variable regions and optionally the constant region genes of murine immunoglobulins have been replaced by their human counterparts, as generally described in European Patent EP0546073, US Patents 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, European Patent EP0438474 and European Patent EP0463151.

[0253] Thus, the presently disclosed anti-interleukin-13 receptor antibodies may comprise one or more constant regions, such as naturally occurring constant domains or derivatives of naturally occurring domains.

[0254] Derivatives of naturally occurring domains as used herein are intended to refer to cases where one, two, three, four or five amino acids are replaced or deleted in the natural sequence, for example to optimize the properties of the domain, such as eliminating undesirable properties while retaining the characteristic features of the domain.

[0255] If desired, the antibodies used in the present invention can be conjugated to one or more effector molecules. It should be understood that the effector molecule can be a single effector molecule or two or more such molecules linked to form a single moiety that can be attached to the antibodies of the present invention. If it is desired to obtain antibody fragments conjugated to effector molecules, this can be prepared by standard chemical or recombinant DNA procedures, in which the antibody fragments are directly or indirectly (including through coupling agents) linked to the effector molecules. Techniques for conjugating such effector molecules to antibodies are well known in the art (see Hellstrom et al., Controlled Release of Biologically Active Agents, 2nd ed., edited by Robinson et al., 1987, pp. 623-653; Thorpe et al., Immunological Reviews, 62:119-158, 1982; Dubowchik et al., Pharmacology & Therapeutics, 83, 67-123, 1999). Specific chemical procedures include, for example, those described in International Publication Patents WO93 / 06231, WO92 / 22583, WO89 / 00195, WO89 / 01476, and WO03 / 031581. Alternatively, if the effector molecule is a protein or polypeptide, the linkage can be achieved using recombinant DNA procedures, such as those described in International Publication Patent WO86 / 01533 and European Patent EP0392745.

[0256] As used herein, the term "effector molecule" includes, for example, biologically active proteins such as enzymes, other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof (such as DNA, RNA and fragments thereof), radionuclides (especially radioiodides), radioisotopes, chelated metals, nanoparticles, and reporter groups such as fluorescent compounds or compounds detectable by nuclear magnetic resonance (NMR) or electron spin resonance (ESR) spectroscopy.

[0257] Other effector molecules may include, for example, detectable substances for diagnosis. Examples of detectable substances include various enzymes, cofactors, fluorescent materials, luminescent materials, bioluminescent materials, radionuclides, positron-emitting metals for positron emission tomography, and non-radioactive paramagnetic metal ions. Regarding metal ions that can bind to antibodies for diagnosis, reference is generally made to U.S. Patent 4,741,900. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; suitable cofactors include streptavidin, avidin, and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinyl aminofluorescein, dansyl chloride, and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; suitable radionuclides include 125I, 131I, 111In, and 99Tc.

[0258] In another example, the effector molecule can increase the half-life of the antibody in vivo, and / or reduce the immunogenicity of the antibody, and / or enhance the delivery of the antibody across an epithelial barrier to the immune system. Examples of such suitable effector molecules include polymers, albumin, albumin-binding proteins or albumin-binding compounds such as those described in International Patent Application Publication No. WO05 / 117984. If the effector molecule is a polymer, generally speaking, it can be a synthetic polymer or a naturally occurring polymer, such as an optionally substituted straight-chain or branched polyalkylene, polyalkenylene or polyoxyalkylene polymer, or a branched or unbranched polysaccharide, such as a homopolysaccharide or a heteropolysaccharide.

[0259] Specific optional substituents that may be present on the above synthetic polymers include one or more hydroxyl groups, methyl groups or methoxy groups.

[0260] Specific examples of synthetic polymers include optionally substituted straight-chain or branched polyethylene glycol, polypropylene glycol, polyvinyl alcohol or derivatives thereof, especially optionally substituted polyethylene glycol, such as methoxypolyethylene glycol or derivatives thereof. Specific examples of naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.

[0261] As used herein, "derivative" is intended to include reactive derivatives, such as thiol-selective reactive groups, such as maleimide and the like. Such reactive groups can be directly or through a linking moiety linked to the polymer. It should be understood that in some cases, residues of such groups will form part of the product as a linking group between the antibody fragment and the polymer.

[0262] Suitable polymers include polyalkylene polymers, such as poly(ethylene glycol), or especially methoxypoly(ethylene glycol) or derivatives thereof, and especially polymers having a molecular weight in the range of about 15,000 Da to about 40,000 Da.

[0263] In one instance, the antibodies used in the present invention are linked to a polyethylene glycol (PEG) moiety. In a specific instance, the antibody is an antibody fragment, and the PEG molecule can be linked through any available amino acid side chain or terminal amino acid functional group located in the antibody fragment, such as any free amino group, imino group, thiol group, hydroxyl group, or carboxyl group. Such amino acids may be naturally present in the antibody fragment or may be engineered into the fragment using recombinant DNA methods (e.g., see U.S. Patent 5,219,996; U.S. Patent 5,667,425; International Publication WO98 / 25971, WO2008 / 038024). In one instance, the antibody molecule of the present invention is a modified Fab fragment, wherein the modification is the addition of one or more amino acids at the C-terminus of its heavy chain to allow the attachment of effector molecules. Suitably, the added amino acids form a modified hinge region containing one or more cysteine residues to which the effector molecule can be attached. Multiple sites can be used to link two or more PEG molecules.

[0264] For patients suffering from cancer (such as breast cancer) and cancer-related lymphedema (BCRL), the formulations of the present invention can prevent lymphedema-related effects such as fibrosis, hyperkeratosis, fibroadipose tissue deposition, fluid retention, limb swelling, reduced skin elasticity, and pain. By reducing the excess volume, the formulations can improve lymphatic function, such as limb function.

[0265] The development of lymphedema after lymphatic injury is associated with tissue inflammation, infiltration of CD4-positive cells, and their differentiation into a type 2 helper T cell (Th2) phenotype. Th2 cells produce interleukin-4 (IL-4) and interleukin-13 (IL-13), which play a key role in the development of lymphedema-related symptoms as well as other Th2-mediated diseases.

[0266] In one embodiment, the formulations described herein are administered in combination with another therapy. As used herein, "in combination" is intended to cover the administration of the anti-interleukin 13 receptor (IL13R) antibody before, concurrently with, or after another therapy, whether in the same or different dosage forms. Thus, "in combination" means that the pharmacological effects of the first therapy and the second therapy are present in the body simultaneously, and / or the two therapies are part of a treatment regimen designed to be used in combination.

[0267] In one embodiment, a loading dose of 600 mg of an anti-interleukin-13 receptor (IL13R) antibody or a binding fragment thereof is administered. In one embodiment, the loading dose is administered for 1 to 3 weeks, such as 1 week, 2 weeks, or 3 weeks. In one embodiment, the loading dose is administered only at week 0. In one embodiment, the loading dose is administered at week 0 and week 1, for example, 600 mg at week 0 and 600 mg at week 1. In one embodiment, the loading dose is administered at week 0, week 1, and week 2, for example, 600 mg at week 0, 600 mg at week 1, and 600 mg at week 2.

[0268] As used herein, a loading dose refers to a higher and / or more frequently administered dose at the start of a treatment cycle. The purpose of a loading dose is to rapidly "saturate" the body's system to achieve the desired drug level for treatment, and this level can be maintained by lower and / or less frequently administered "therapeutic" doses. In some embodiments, this effect may be achieved more rapidly locally by concentrating the administration at the same site in the body. The subsequent dose administered after the loading dose is referred to herein as the therapeutic dose.

[0269] As used herein, a "therapeutic dose" refers to the amount of an anti-interleukin-13 receptor (IL13R) antibody (such as ASLAN004) that, when used in a suitable treatment regimen, is capable of achieving the desired therapeutic effect, such as improving the symptoms or condition of a disease, and in particular, does not cause dose-limiting side effects. A suitable therapeutic dose is typically a balance between therapeutic effect and tolerable toxicity, for example, the side effects and toxicity are tolerable considering the benefits of the treatment.

[0270] In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or a binding fragment thereof is 300 mg. In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or a binding fragment thereof is 300 mg administered every 2 weeks (300 mg Q2W). In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or a binding fragment thereof is 300 mg administered every 4 weeks (300 mg Q4W).

[0271] In one embodiment, the therapeutic dose of the anti-IL13R antibody or a binding fragment thereof is 400 mg. In one embodiment, the therapeutic dose of the anti-IL13R antibody or a binding fragment thereof is 400 mg administered every two weeks (400 mg, once every 2 weeks). In one embodiment, the therapeutic dose of the inhibitor is 400 mg administered every four weeks (400 mg, once every 4 weeks).

[0272] In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or its binding fragment is 600 mg. In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or its binding fragment is administered at 600 mg every two weeks (600 mg Q2W). In one embodiment, the therapeutic dose of the anti-interleukin-13 receptor antibody or its binding fragment is administered at 600 mg every four weeks (600 mg Q4W).

[0273] In one embodiment, the dosage of the anti-interleukin-13 receptor antibody or its binding fragment is 300 mg once every two weeks (300 mg Q2W), 400 mg once every two weeks (400 mg Q2W), 400 mg once every four weeks (400 mg Q4W), or 600 mg once every four weeks (600 mg Q4W). In one embodiment, the dosage of the anti-interleukin-13 receptor antibody or its binding fragment is 300 mg once every two weeks (300 mg Q2W), 400 mg once every two weeks (400 mg Q2W), or 600 mg once every four weeks (600 mg Q4W). In one embodiment, the anti-interleukin-13 receptor antibody or its binding fragment is not administered at a dosage of 400 mg once every four weeks (400 mg Q4W).

[0274] In one embodiment, 600 mg of the anti-interleukin 13 receptor (IL13R) antibody or its binding fragment is administered at week 0 and week 1 as a loading dose, and then 300 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered every two weeks. In one embodiment, 600 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered at week 0 and week 1 as a loading dose, and then 400 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered every two weeks. In one embodiment, 600 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered at week 0, week 1, and week 2 as a loading dose, and then 400 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered every four weeks. In one embodiment, 600 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered at week 0, week 1, and week 2 as a loading dose, and then 600 mg of the anti-interleukin 13 receptor antibody or its binding fragment is administered every four weeks.

[0275] In one embodiment, the preparation of the present invention (including the formulation containing the preparation) is administered once a month, for example, during a treatment cycle or as maintenance therapy.

[0276] As used herein, the "treatment cycle" refers to a complete cycle including a loading dose and a treatment dose over a defined period of time, such as 1 month or longer, 2 months or longer; or 3 months or longer, such as 4, 5 or 6 months. After treatment interruption, the cycle can be restarted, starting again from the loading dose.

[0277] In one embodiment, a maintenance dose is used after the treatment cycle to keep the disease in remission.

[0278] The unit dose as used herein generally refers to a product that contains an amount of the anti - interleukin - 13 receptor (IL13R) antibody or its binding fragment for a single administration of the present invention, including any excess portion. The unit dose of the anti - interleukin - 13 receptor (IL13R) antibody or its antigen - binding fragment claimed in the present invention may refer to the marketed form of the product, such as a formulation of the anti - interleukin - 13 receptor (IL13R) antibody or its binding fragment, wherein the product is formulated to the amount of the anti - interleukin - 13 receptor (IL13R) antibody required for a single administration. Thus, the manufacturer can determine and control the exact amount of the anti - interleukin - 13 receptor (IL13R) antibody or its binding fragment contained in each unit dose.

[0279] The product can have various forms well - known to those skilled in the art, such as vials, ampoules, infusion bags or devices (including auto - injection devices). The "exact amount" as used herein refers to the amount administered to a patient as a single dose and any remainder.

[0280] In one embodiment, the unit dose or multiple unit doses are used according to a method of the present invention.

[0281] In the context of this specification, "comprising" should be construed as "including".

[0282] Embodiments of the present invention that include certain features / elements are also intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the relevant elements / features. Where technically appropriate, embodiments of the present invention can be combined.

[0283] Technical references such as patents and applications are incorporated herein by reference.

[0284] Any embodiment specifically and expressly recited herein can form the basis of a disclaimer, either alone or in combination with one or more other embodiments.

[0285] The background section of this specification contains relevant technical information and can be used as a basis for modification.

[0286] This application claims priority to U.S. Patent Application No. 63 / 374,678, filed on September 6, 2022, which is incorporated herein by reference and can be used to correct errors in this specification.

[0287] Individual numerical values or elements in the examples can be extracted and combined with the general elements of the present invention, that is, they can be used as specific bases for modification without referring to other features of the examples.

[0288] The subject headings herein are used to divide the document into multiple parts and are not intended to explain the meaning of the disclosure provided herein.

[0289] The present invention is further illustrated below only by way of example.

[0290] Brief Description of the Drawings

[0291] Figure 1A Demographics of the full analysis set

[0292] Figure 1B Table showing baseline disease characteristics of the full analysis set

[0293] Figure 1C Table showing baseline disease characteristics of the evaluable efficacy set (EES)

[0294] Figure 2A Table showing the percentage change in EASI score of the evaluable efficacy set (EES) relative to baseline at day 57.

[0295] Figure 2B Graph showing the percentage change in EASI score of the evaluable efficacy set (EES) relative to baseline at day 57 (ASLAN004 200mg, 400mg, and 600mg).

[0296] Figure 2C Graph showing the percentage change in EASI score of the evaluable efficacy set (EES) relative to baseline at day 57 (ASLAN004 low dose and high dose).

[0297] Figure 3A Table showing the percentage change in EASI score of the evaluable efficacy set (EES) relative to baseline at day 29.

[0298] Figure 3B Graph showing the percentage change in EASI score of the evaluable efficacy set (EES) relative to baseline at day 29 (ASLAN004 200mg, 400mg, and 600mg).

[0299] Figure 4APercentage chart of EASI scores showing the Evaluable Efficacy Set (EES) over time (ASLAN004 200mg, 400mg, and 600mg).

[0300] Figure 4B Percentage chart of EASI scores showing the Evaluable Efficacy Set (EES) over time (ASLAN004 low dose and high dose).

[0301] Figure 5A Chart showing the percentage change in EASI scores relative to baseline over time for the EES (placebo group).

[0302] Figure 5B Chart showing the percentage change in EASI scores relative to baseline over time for the EES (ASLAN004 200mg group).

[0303] Figure 5C Chart showing the percentage change in EASI scores relative to baseline over time for the EES (ASLAN004 400mg group).

[0304] Figure 5D Chart showing the percentage change in EASI scores relative to baseline over time for the EES (ASLAN004 600mg group).

[0305] Figure 6A Table showing the sensitivity analysis of the modified intention-to-treat (mITT) group on Day 57

[0306] Figure 6B Chart showing the results of the sensitivity analysis of the mITT (ASLAN004 200mg, 400mg, and 600mg groups) on Day 57

[0307] Figure 6C Chart showing the results of the sensitivity analysis of the mITT (ASLAN004 low dose and high dose groups) on Day 57

[0308] Figure 7A Summary table showing the EASI 50, EASI 75, and EASI 90 situations of the EES (Evaluable Efficacy Set) on Day 57

[0309] Figure 7B Chart showing the EASI 50 situation of the EES (ASLAN004 200mg, 400mg, and 600mg groups) on Day 57

[0310] Figure 7C Chart showing the EASI 50 situation of the EES (ASLAN004 low dose and high dose groups) on Day 57

[0311] Figure 7DChart showing the EASI 75 status of EES (ASLAN004 200mg, 400mg, and 600mg groups) on Day 57

[0312] Figure 7E Chart showing the EASI 75 status of EES (ASLAN004 low-dose and high-dose groups) on Day 57

[0313] Figure 7F Chart showing the EASI 90 status of EES (ASLAN004 200mg, 400mg, and 600mg groups) on Day 57

[0314] Figure 7G Chart showing the EASI 90 status of EES (ASLAN004 low-dose and high-dose groups) on Day 57

[0315] Figure 8A Chart showing the proportion of patients achieving a 50% improvement in EASI

[0316] Figure 8B Chart showing the proportion of patients achieving a 75% improvement in EASI

[0317] Figure 8C Chart showing the proportion of patients achieving a 90% improvement in EASI

[0318] Figure 9 Summary table showing the proportion of patients achieving EASI 50, 75, and 90 in EES and mITT

[0319] Figure 10A Summary table showing the proportion of patients with an IGA score of 0 or 1 for ESS on Day 57

[0320] Figure 10B Chart showing the proportion of patients with an IGA score of 0 or 1 for ESS on Day 57

[0321] Figure 10C Chart showing the proportion of patients with an IGA score of 0 or 1 for ESS over time

[0322] Figure 11 Table showing the baseline TARC and IgE levels of patients

[0323] Figure 12A Chart showing the mean percentage change in TARC relative to baseline for the ASLAN004 200mg and 400mg groups

[0324] Figure 12B Chart showing the mean percentage change in TARC relative to baseline for the ASLAN004 400mg group and the placebo group

[0325] Figure 12C Chart showing the percentage change in TARC relative to baseline for individual patients in the ASLAN004 400 mg group

[0326] Figure 13A Chart showing the percentage change in IgE relative to baseline for the ASLAN004 200 mg and 400 mg groups

[0327] Figure 13B Chart showing the percentage change in mean IgE relative to baseline for the ASLAN004 200 mg and 400 mg groups

[0328] Figure 13C Chart showing the percentage change in IgE relative to baseline for individual patients in the placebo group

[0329] Figure 13D Chart showing the percentage change in IgE relative to baseline for individual patients in the ASLAN004 200 mg group

[0330] Figure 13E Chart showing the percentage change in IgE relative to baseline for individual patients in the ASLAN004 400 mg group

[0331] Figure 14 Chart showing the ASLAN004 exposure, Eczema Area and Severity Index (EASI), Thymus and Activation Regulated Chemokine (TARC), and Immunoglobulin E (IgE) over time in patients treated with ASLAN004 400 mg

[0332] Figure 15 Table showing the comparison between ASLAN004 and dupilumab

[0333] Figure 16 Flowchart showing the number of subjects in each test group

[0334] Figure 17 Table showing the baseline demographics and disease characteristics of the Intention-to-Treat (ITT) group, Modified Intention-to-Treat (mITT) group, and Excluded Sites group

[0335] Figure 18 Table showing the Adverse Events (AEs) in the Modified Intention-to-Treat (mITT) group and Excluded Sites group

[0336] Figure 19A Chart showing the improvement in the most severe pruritus over time (median) in the mITT group

[0337] Figure 19B Chart showing the improvement in the most severe pruritus at week 8 (median) in the mITT group

[0338] Figure 20A Chart showing the mean improvement in itching over time (median) in the mITT group

[0339] Figure 20B Chart showing the mean improvement in itching at week 8 (median) in the mITT group

[0340] Figure 21 Chart showing the improvement in POEM score relative to baseline (change from baseline, CFBL) over time

[0341] Figure 22 Chart showing a 2 - point improvement in sleep disorder (SD) score at week 8 in the mITT group

[0342] Figure 23 Table showing the baseline characteristics of patients in the intention - to - treat (ITT) population in the TREK - AD study

[0343] a =Ixekizumab 400 mg every four weeks (Q4W) (n = 59); Ixekizumab 600 mg every four weeks (n = 57); Ixekizumab 300 mg every two weeks (Q2W) (n = 58); Ixekizumab 400 mg every two weeks (n = 55); Placebo every two weeks (n = 56); All ixekizumab groups

[0344] (n = 229)

[0345] b =Ixekizumab 400 mg every four weeks (Q4W) (n = 24); Ixekizumab 600 mg every four weeks (n = 21); Ixekizumab 300 mg every two weeks (Q2W) (n = 20); Ixekizumab 400 mg every two weeks (n = 19); Placebo every two weeks (n = 23); All ixekizumab groups (n = 84)

[0346] c =Ixekizumab 400 mg every four weeks (Q4W) (n = 24); Ixekizumab 600 mg every four weeks (n = 20); Ixekizumab 300 mg every two weeks (Q2W) (n = 20); Ixekizumab 400 mg every two weeks (n = 19); Placebo every two weeks (n = 23); All ixekizumab groups

[0347] (n = 83)

[0348] BSA, body surface area; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index

[0349] Count; IGA, Investigator's Global Assessment (on a 5-point scale); NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure; Q2W, every two weeks; Q4W, every four weeks; SD, Standard Deviation

[0350] Figure 24 Graph showing the percentage change from baseline in the sleep deprivation component of the SCORAD (Severity of Atopic Dermatitis Index) in patients in the intention-to-treat (ITT) population over 16 weeks from the TREK-AD study

[0351] Figure 25A Graph showing the proportion of patients in the intention-to-treat (ITT) population with a change of ≥4 points in the Sleep Disturbance Numerical Rating Scale (SD NRS) over the 16-week study period from baseline SD NRS

[0352] Figure 25B Graph showing the proportion of patients with a baseline Sleep Disturbance Numerical Rating Scale (SD NRS) score in the intention-to-treat (ITT) group who had a change of ≥4 points in the Sleep Disturbance Numerical Rating Scale at Week 16

[0353] Example

[0354] Example 1 Study Protocol (Initial Maximum Tolerated Dose Escalation)

[0355] Patients (doses received) in the ASLAN004 dose escalation cohorts (sequence numbers 51, 53, and 59 in this document): 200 mg, 400 mg, 600 mg. Initially these doses were administered once weekly. In each cohort, patients were randomized in a 3:1 ratio of ASLAN004 to placebo

[0356] Table 1 Baseline Thymus and Activation Regulated Chemokine (TARC) and Immunoglobulin E (IgE) Levels

[0357]

[0358] Figure 13A Shows the percent change from baseline in all treated patients on Days 15, 29, 43, and 57 Figure 13B Shows the mean percent change from baseline over the same period

[0359] Figure 13C Panels A to E show individual patient data

[0360] Table 2 shows the reduction and negativity of IgE levels

[0361]

[0362] It can be seen that in the highly allergic patient population (IgE 41.6% cfbl), ASLAN004 reduced IgE levels by -34%. In fact, this reduction is more significant than the -15% to -30% reduction achieved by dupilumab in the population with lower allergic reactions.

[0363] Example 2

[0364] Among the 32 patients (defined as the efficacy evaluation dataset in the protocol) who completed at least 29 days of dosing at all study sites, the mean reduction in the Eczema Area and Severity Index (EASI) at 8 weeks compared to baseline was 73% (n = 19) in the treatment group and 44% (n = 13) in the placebo group (p = 0.0071).

[0365] The proportion of patients experiencing adverse events and treatment-related adverse events was similar in the treatment and placebo groups. There were no cases of conjunctivitis in the expanded cohort.

[0366] Table 3 - Results of the Revised Intent-to-Treat (RITT) Group and Intent-to-Treat (ITT) Group

[0367]

[0368] 1 One-sided p-value

[0369] Compared with placebo, ASLAN004 achieved a statistically significant improvement in the primary efficacy endpoint of the percentage change in Eczema Area and Severity Index (EASI) compared to baseline (p < 0.025), and also showed significant improvement in other key efficacy endpoints (p < 0.05): 50% reduction in EASI, 75% reduction in EASI, peak pruritus, and Patient-Oriented Eczema Measure (POEM).

[0370] After discussion with the Data Monitoring Committee before unblinding, a revised intent-to-treat population (RITT, n = 29) was determined by excluding one study site. Based on biomarkers (such as TARC) and patient history, all patients included in this study site did not seem typical and did not belong to patients with moderate to severe atopic dermatitis (AD). Compared with other published studies on moderate to severe AD, the RITT population was more comparable. In this population, ASLAN004 also achieved a statistically significant improvement in the percentage change in Eczema Area and Severity Index (EASI) compared to baseline compared with placebo (p < 0.025), and showed more significant improvement compared with placebo in key efficacy endpoints compared with the intent-to-treat population.

[0371] Example 3

[0372] The objective of this study was to evaluate the effect of ixekizumab on itch and sleep scores in patients with atopic dermatitis (AD).

[0373] Methods

[0374] In a multi-dose escalating study design, three patient cohorts were randomly assigned to receive subcutaneous injections of 200, 400, or 600 mg of ixekizumab or placebo once weekly for 8 weeks.

[0375] The adult patients included had had chronic atopic dermatitis (AD) for ≥3 years before screening and had the following atopic dermatitis parameters at screening and baseline: Eczema Area and Severity Index (EASI) ≥16,

[0376] Investigator Global Assessment (IGA) score ≥3 (on a scale of 0 to 4), and atopic dermatitis (AD) involving ≥10% of the body surface area (BSA). Use of rescue medications (moisturizers containing active ingredients, topical glucocorticoids, topical calcineurin inhibitors) was not permitted; for participants using rescue medications, the last observation carried forward (LOCF) method was used.

[0377] Patient-reported outcomes were measured, including the Pruritus Numerical Rating Scale (P-NRS) for worst and mean itch, and the Patient-Oriented Eczema Measure (POEM), which includes a single-item sleep loss subscale.

[0378] Inferential statistical analysis was performed only on the 600 mg dose group and the placebo group at week 8.

[0379] Due to the small sample size, the results of the 200 mg group and the 400 mg group were described descriptively. In the efficacy analysis of the phase 1b study, a modified intention-to-treat (mITT) population was used, in which 9 study patients from one study site (excluded study site group) were excluded from the intention-to-treat (ITT) analysis before unblinding because these participants did not have disease characteristics consistent with moderate to severe atopic dermatitis ( Figure 16 ).

[0380] Results

[0381] At baseline, the excluded study site group was significantly different from the modified intention-to-treat (mITT) group, with significantly lower serum thymus and activation-regulated chemokine / CCL17 (7,350 pg / L and 461 pg / L, respectively), serum immunoglobulin E (12,225 KU / L and 527 KU / L, respectively), and eczema area and severity index (means of 31.2 and 19.3, respectively), indicating a lower degree and severity of the disease. Other significant differences included older age and lower scores on the Investigator Global Assessment (IGA), body surface area (BSA) involved, and Patient-Oriented Eczema Measure (POEM). Participants at this study site had no history of atopic disease but reported other comorbidities, including diabetes and hypertension( Figure 17 ).

[0382] In the intention-to-treat analysis dataset (mITT), over time, at week 8 ( Figure 19A and 19B ), compared with the placebo group, the isakizumab treatment group had a significant improvement in the percentage change from baseline (%CFBL) of the Pruritus Numerical Rating Scale (P-NRS) for the median of the worst pruritus; there was also a significant improvement for the median of the mean pruritus ( Figure 20A and 20B ) (worst pruritus: -48% in the isakizumab 600 mg group vs -13% in the placebo group; mean pruritus: -49% in the isakizumab 600 mg group vs -6% in the placebo group).

[0383] In the "excluded site" group, participants treated with 600 mg of isakizumab had improvement in mean pruritus symptoms compared with the placebo group, but no improvement in the worst pruritus symptoms.

[0384] In the modified intention-to-treat (mITT) analysis set, compared with placebo, over time, the Patient-Oriented Eczema Measure (POEM) scores of patients treated with isakizumab improved significantly. The magnitude of the treatment response for the 400 mg and 600 mg doses was greater than that for the 200 mg dose ( Figure 21 ). At week 8, the median changes in POEM from baseline were -12 and -9 in the 400 mg and 600 mg isakizumab treatment groups, respectively, compared with -1 in the placebo group in the mITT analysis set. In the excluded study site group, no improvement was observed compared with placebo.

[0385] In the modified intention-to-treat (mITT) analysis set, at week 8, compared with the placebo group, the Patient-Oriented Eczema Measure (POEM) score improved by 4 points in the ixekizumab 600 mg treatment group, but this was not observed in the per-protocol analysis set (81% vs. 23%; 50% vs. 100%, respectively). Ixekizumab had a greater effect in improving the POEM sleep score compared with placebo ( Figure 22 ). In the mITT analysis set, at week 8, the 400 mg and 600 mg ixekizumab treatment groups had an improvement of 2 points (mean) in sleep insufficiency (one item in POEM) (43% and 56% vs. 15% for placebo, respectively), and in the per-protocol group, the 600 mg ixekizumab treatment group also had an improvement (33% vs. 0% for placebo).

[0386] Importantly, these were improvements in patients with a baseline sleep disorder score of 3 or 4. Most patients (75% [12 / 16]) in the 600 mg treatment group reported more than 5 nights of sleep disorder at baseline, compared with 54% [7 / 13] in the placebo group. More patients treated with ixekizumab (63% [10 / 16]) reported "no days with sleep disorder" or "1 - 2 days with sleep disorder" at week 8 compared with the placebo group (38% [5 / 13]).

[0387] The use of rescue medications was lower, but higher in the placebo group (data not shown).

[0388] The incidence of moderate to severe adverse events (AEs) was comparable between the 600 mg dose group and the placebo group. Treatment-related adverse events were similar between groups ( Figure 18 ).

[0389] Interestingly, the adverse events leading to treatment discontinuation had a higher incidence in the placebo group. One serious adverse event (SAE) (mild abdominal pain, 400 mg) was reported in the study; it was considered not related to the treatment. No deaths were reported.

[0390] Conclusion

[0391] This study showed that in a phase 1b study of adult patients with moderate to severe atopic dermatitis, ixekizumab was well tolerated and had significant improvements in multiple efficacy measures compared with placebo. In particular, the sleep disorder score was significantly improved in patients treated with ixekizumab compared with those treated with placebo. Sensitivity analysis of the primary analysis data set confirmed the reliability of the data from this small study. Inclusion or exclusion of study site data did not change the primary endpoint or the study conclusion.

[0392] These significant improvements were observed over the 8-week study period, suggesting that longer treatment durations may result in greater degrees of efficacy, which supports further investigation in the ongoing Phase 2b clinical trial.

[0393] Example 4

[0394] The TREK-AD (Trial of Ixekizumab in Atopic Dermatitis) study was a randomized, double-blind, placebo-controlled, dose-ranging Phase 2b clinical trial designed to evaluate the efficacy and safety of ixekizumab as monotherapy in adult patients with moderate to severe atopic dermatitis (AD) who had not received biologic therapy and were suitable for systemic treatment. The baseline characteristics of the intention-to-treat (ITT) group are shown in Figure 23 .

[0395] During the TREK-AD study, various clinical analyses were conducted, including changes in the Eczema Area and Severity Index (EASI), the Scoring Atopic Dermatitis Index (SCORAD), the Dermatology Life Quality Index (DLQI), the Patient-Oriented Eczema Measure (POME), the EQ-5D-5L, and the Hospital Anxiety and Depression Scale (HAD), as well as the proportion of patients with a 4-point reduction in the Sleep Disturbance Numerical Rating Scale (SD-NRS) from baseline to Week 16. The results of the change in the sleep deprivation component of SCORAD and the proportion of patients with a 4-point reduction in SD-NRS from baseline to Week 16 are shown in Figure 24 and Figure 25.

[0396] Figure 24 Clearly demonstrate that ixekizumab can improve sleep disturbances, as measured by individual component scores of the Scoring Atopic Dermatitis Index (SCORAD) quality of life measurement. Specifically, when ixekizumab was administered at dosing regimens of 400 mg every four weeks (400 mg Q4W), 600 mg every four weeks (600 mg Q4W), 300 mg every two weeks (300 mg Q2W), and 400 mg every four weeks (400 mg Q4W), the changes in sleep deprivation scores from baseline were -37.7%, -50.6%, -37.3%, and -52.2%, respectively.

[0397] Figure 25 shows that a large proportion of patients were able to achieve a 4-point or greater reduction in the Sleep Disturbance Numerical Rating Scale (SD-NRS) relative to baseline at Week 16 (a 4-point reduction in SD-NRS represents a clinically significant improvement). In particular, 32.3% of patients receiving ixekizumab 300 mg every 2 weeks, meaning that almost one-third of the patients in this treatment group had an SD-NRS change of 4 points or more.

[0398] Therefore, the results of the TREK-AD study further demonstrate the potential of ixekizumab to significantly improve sleep loss / sleep deprivation in patients.

Claims

1. An antibody or antigen-binding fragment thereof that inhibits signal transduction by binding to interleukin-13 receptor alpha 1 (IL-13Rα1), for treating sleep deprivation or sleep disorders in a patient by parenteral administration for one treatment cycle (dose range from 200 mg to 600 mg, such as 300, 400, 500 or 600 mg, e.g., 400 to 600 mg). For example, the treatment can reduce the sleep disorder (SD) score in the Patient-Oriented Eczema Measure (POEM), e.g., by -50% to -100% relative to baseline, such as a reduction of 2 to 4 points relative to baseline.

2. The antibody or antigen-binding fragment thereof for treatment according to claim 1, wherein the treatment reduces the sleep disorder (SD) score in the Patient-Oriented Eczema Measure (POEM), e.g., by -50% to -100% relative to baseline, such as a reduction of 2 to 4 points relative to baseline.

3. The antibody or antigen-binding fragment thereof used according to any one of the preceding claims, wherein the patient's baseline sleep disorder (SD) score is at least 3 points, such as 3 points or 4 points.

4. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the sleep disorder (SD) score is reduced by 2 to 4 points relative to baseline, such as 2 points, 3 points or 4 points.

5. The antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 4, wherein the treatment reduces the sleep deprivation subscale of the Scoring Atopic Dermatitis (SCORAD), e.g., by -20% to -100% relative to baseline, such as a reduction of 2 points or more, e.g., a reduction of 2, 3, 4, 5, 6, 7, 8, 9 or 10 points relative to baseline.

6. The antibody or antigen-binding fragment thereof used according to claim 5, wherein the patient's baseline sleep deprivation score of the Scoring Atopic Dermatitis (SCORAD) is at least 4 points, such as 4, 5, 6, 7, 8, 9 or 10 points.

7. The antibody or antigen-binding fragment thereof for treatment according to claim 5 or 6, wherein the sleep deprivation subscale of the Scoring Atopic Dermatitis (SCORAD) is reduced by -30% to -60% relative to baseline, such as a reduction of -30%, -35%, -40%, -45%, -50%, -55% or -60%.

8. The antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 7, wherein the treatment reduces the Sleep Disorder Numerical Rating Scale (SD NRS), e.g., by -20% to -100% relative to baseline, such as a reduction of 4 points or more, e.g., a reduction of 4, 5, 6, 7, 8, 9 or 10 points relative to baseline.

9. The antibody or antigen-binding fragment thereof for treatment according to claim 8, wherein the patient's baseline score on the Sleep Disorder Numerical Rating Scale (SD NRS) is at least 4 points, such as 4, 5, 6, 7, 8, 9 or 10 points from baseline.

10. The antibody or antigen-binding fragment thereof for treatment according to claim 5 or 6, wherein the sleep disorder numerical rating scale (SD NRS) is reduced by 4 points or more, such as 4, 5, 6, 7, 8, 9 or 10 points from baseline.

11. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the patient is a highly allergic patient, for example, the baseline immunoglobulin E (IgE) level has been confirmed and the level is at least 10,000 KU / L ± 2,000.

12. The antibody or binding fragment according to any one of claims 1 to 11, wherein a reduction in the sleep disorder (SD) score, the sleep deprivation score of the SCORAD (SCORing Atopic Dermatitis) or the SD NRS score is observed at about day 15.

13. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the patient has pruritus.

14. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the patient has a skin disease, for example selected from the group consisting of: dermatitis, such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis; eczema; hand, foot and mouth disease; urticaria (including urticaria associated with lupus), psoriasis, infections, such as fungal infections or bacterial infections, for example impetigo or folliculitis; allergic skin reactions; Ehlers-Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE).

15. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the patient has atopic dermatitis (AD), for example moderate to severe atopic dermatitis.

16. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein the treatment is administered by subcutaneous injection.

17. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein multiple doses are administered within one treatment cycle (for example, wherein the treatment cycle is 4 to 8 weeks, such as 8 weeks).

18. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein multiple treatment cycles are carried out, for example 2, 3, 4 or more treatment cycles are carried out.

19. The antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 18, wherein the antibody or its binding fragment is administered approximately once every two weeks (especially within a single treatment cycle, especially 8 weeks).

20. The antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 18, wherein the antibody or its binding fragment is administered approximately once every four weeks (for example once a month) (especially within a single treatment cycle, especially 8 weeks).

21. The antibody or antigen-binding fragment thereof for treatment according to any one of the preceding claims, wherein a loading dose of 400 to 900 mg is used before administration within the treatment cycle, for example 400, 500, 600, 700, 800 or 900 mg.

22. An antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 21, wherein the dose is 300 mg.

23. An antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 21, wherein the dose is 400 mg.

24. An antibody or antigen-binding fragment thereof for treatment according to any one of claims 1 to 21, wherein the dose is 600 mg.

25. An antibody or antigen-binding fragment thereof for treatment according to any of the preceding claims, wherein the antibody comprises a light chain variable region (VL) having the amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, particularly SEQ ID NO: 53, and a heavy chain variable region (VH) having the amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, particularly SEQ ID NO:

51.

26. An antibody or antigen-binding fragment thereof for treatment according to any of the preceding claims, wherein the antibody is ixekizumab.

Images